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Di Stefano J, Di Marco F, Cicalini I, FitzGerald U, Pieragostino D, Verhoye M, Ponsaerts P, Van Breedam E. Generation, interrogation, and future applications of microglia-containing brain organoids. Neural Regen Res 2025; 20:3448-3460. [PMID: 39665813 PMCID: PMC11974650 DOI: 10.4103/nrr.nrr-d-24-00921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 12/13/2024] Open
Abstract
Brain organoids encompass a large collection of in vitro stem cell-derived 3D culture systems that aim to recapitulate multiple aspects of in vivo brain development and function. First, this review provides a brief introduction to the current state-of-the-art for neuro-ectoderm brain organoid development, emphasizing their biggest advantages in comparison with classical two-dimensional cell cultures and animal models. However, despite their usefulness for developmental studies, a major limitation for most brain organoid models is the absence of contributing cell types from endodermal and mesodermal origin. As such, current research is highly investing towards the incorporation of a functional vasculature and the microglial immune component. In this review, we will specifically focus on the development of immune-competent brain organoids. By summarizing the different approaches applied to incorporate microglia, it is highlighted that immune-competent brain organoids are not only important for studying neuronal network formation, but also offer a clear future as a new tool to study inflammatory responses in vitro in 3D in a brain-like environment. Therefore, our main focus here is to provide a comprehensive overview of assays to measure microglial phenotype and function within brain organoids, with an outlook on how these findings could better understand neuronal network development or restoration, as well as the influence of physical stress on microglia-containing brain organoids. Finally, we would like to stress that even though the development of immune-competent brain organoids has largely evolved over the past decade, their full potential as a pre-clinical tool to study novel therapeutic approaches to halt or reduce inflammation-mediated neurodegeneration still needs to be explored and validated.
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Affiliation(s)
- Julia Di Stefano
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
- Bio-Imaging Lab, University of Antwerp, Wilrijk, Belgium
| | - Federica Di Marco
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Ilaria Cicalini
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Una FitzGerald
- CÚRAM, Center for Research in Medical Devices, Biomedical Engineering, University of Galway, Ireland
- Galway Neuroscience Center, University of Galway, Ireland
| | - Damiana Pieragostino
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Marleen Verhoye
- Bio-Imaging Lab, University of Antwerp, Wilrijk, Belgium
- μNEURO Research Center of Excellence, University of Antwerp, Wilrijk, Belgium
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
| | - Elise Van Breedam
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
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Antico O, Thompson PW, Hertz NT, Muqit MMK, Parton LE. Targeting mitophagy in neurodegenerative diseases. Nat Rev Drug Discov 2025; 24:276-299. [PMID: 39809929 DOI: 10.1038/s41573-024-01105-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2024] [Indexed: 01/16/2025]
Abstract
Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.
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Affiliation(s)
- Odetta Antico
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Paul W Thompson
- Mission Therapeutics Ltd, Babraham Research Campus, Cambridge, UK
| | | | - Miratul M K Muqit
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Laura E Parton
- Mission Therapeutics Ltd, Babraham Research Campus, Cambridge, UK.
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Kim MS, Yoon S, Choi J, Kim YJ, Lee G. Stem Cell-Based Approaches in Parkinson's Disease Research. Int J Stem Cells 2025; 18:21-36. [PMID: 38449089 PMCID: PMC11867902 DOI: 10.15283/ijsc23169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 03/08/2024] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of midbrain dopaminergic neurons, leading to motor symptoms. While current treatments provide limited relief, they don't alter disease progression. Stem cell technology, involving patient-specific stem cell-derived neurons, offers a promising avenue for research and personalized regenerative therapies. This article reviews the potential of stem cell-based research in PD, summarizing ongoing efforts, their limitations, and introducing innovative research models. The integration of stem cell technology and advanced models promises to enhance our understanding and treatment strategies for PD.
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Affiliation(s)
- Min Seong Kim
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Subeen Yoon
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea
| | - Jiwoo Choi
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea
| | - Yong Jun Kim
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea
- Department of Pathology, College of Medicine, Kyung Hee University, Seoul, Korea
- KHU-KIST Department of Converging Science and Technology, Graduate School, Kyung Hee University, Seoul, Korea
| | - Gabsang Lee
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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4
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Jiao F, Meng L, Du K, Li X. The autophagy-lysosome pathway: a potential target in the chemical and gene therapeutic strategies for Parkinson's disease. Neural Regen Res 2025; 20:139-158. [PMID: 38767483 PMCID: PMC11246151 DOI: 10.4103/nrr.nrr-d-23-01195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 11/14/2023] [Accepted: 12/06/2023] [Indexed: 05/22/2024] Open
Abstract
Parkinson's disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such as α-synuclein in neurons. As one of the major intracellular degradation pathways, the autophagy-lysosome pathway plays an important role in eliminating these proteins. Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance of α-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson's disease. Moreover, multiple genes associated with the pathogenesis of Parkinson's disease are intimately linked to alterations in the autophagy-lysosome pathway. Thus, this pathway appears to be a promising therapeutic target for treatment of Parkinson's disease. In this review, we briefly introduce the machinery of autophagy. Then, we provide a description of the effects of Parkinson's disease-related genes on the autophagy-lysosome pathway. Finally, we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy-lysosome pathway and their applications in Parkinson's disease.
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Affiliation(s)
- Fengjuan Jiao
- School of Mental Health, Jining Medical University, Jining, Shandong Province, China
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, Shandong Province, China
| | - Lingyan Meng
- School of Mental Health, Jining Medical University, Jining, Shandong Province, China
| | - Kang Du
- School of Mental Health, Jining Medical University, Jining, Shandong Province, China
| | - Xuezhi Li
- School of Mental Health, Jining Medical University, Jining, Shandong Province, China
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, Shandong Province, China
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Lal R, Singh A, Watts S, Chopra K. Experimental models of Parkinson's disease: Challenges and Opportunities. Eur J Pharmacol 2024; 980:176819. [PMID: 39029778 DOI: 10.1016/j.ejphar.2024.176819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 05/29/2024] [Accepted: 07/17/2024] [Indexed: 07/21/2024]
Abstract
Parkinson's disease (PD) is a widespread neurodegenerative disorder occurs due to the degradation of dopaminergic neurons present in the substantia nigra pars compacta (SNpc). Millions of people are affected by this devastating disorder globally, and the frequency of the condition increases with the increase in the elderly population. A significant amount of progress has been made in acquiring more knowledge about the etiology and the pathogenesis of PD over the past decades. Animal models have been regarded to be a vital tool for the exploration of complex molecular mechanisms involved in PD. Various animals used as models for disease monitoring include vertebrates (zebrafish, rats, mice, guinea pigs, rabbits and monkeys) and invertebrate models (Drosophila, Caenorhabditis elegans). The animal models most relevant for study of PD are neurotoxin induction-based models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-Hydroxydopamine (6-OHDA) and agricultural pesticides (rotenone, paraquat), pharmacological models (reserpine or haloperidol treated rats), genetic models (α-synuclein, Leucine-rich repeat kinase 2 (LRRK2), DJ-1, PINK-1 and Parkin). Several non-mammalian genetic models such as zebrafish, Drosophila and Caenorhabditis elegance have also gained popularity in recent years due to easy genetic manipulation, presence of genes homologous to human PD, and rapid screening of novel therapeutic molecules. In addition, in vitro models (SH-SY5Y, PC12, Lund human mesencephalic (LUHMES) cells, Human induced pluripotent stem cell (iPSC), Neural organoids, organ-on-chip) are also currently in trend providing edge in investigating molecular mechanisms involved in PD as they are derived from PD patients. In this review, we explain the current situation and merits and demerits of the various animal models.
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Affiliation(s)
- Roshan Lal
- Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
| | - Aditi Singh
- TR(i)P for Health Laboratory, Centre for Excellence in Functional Foods, Department of Food and Nutritional Biotechnology, National Agri-Food Biotechnology Institute (NABI), Knowledge City, Sector 81, SAS Nagar, Punjab, 140306, India.
| | - Shivam Watts
- Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
| | - Kanwaljit Chopra
- Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
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6
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Basso V, Döbrössy MD, Thompson LH, Kirik D, Fuller HR, Gates MA. State of the Art in Sub-Phenotyping Midbrain Dopamine Neurons. BIOLOGY 2024; 13:690. [PMID: 39336117 PMCID: PMC11428604 DOI: 10.3390/biology13090690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/30/2024]
Abstract
Dopaminergic neurons in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNpc) comprise around 75% of all dopaminergic neurons in the human brain. While both groups of dopaminergic neurons are in close proximity in the midbrain and partially overlap, development, function, and impairments in these two classes of neurons are highly diverse. The molecular and cellular mechanisms underlying these differences are not yet fully understood, but research over the past decade has highlighted the need to differentiate between these two classes of dopaminergic neurons during their development and in the mature brain. This differentiation is crucial not only for understanding fundamental circuitry formation in the brain but also for developing therapies targeted to specific dopaminergic neuron classes without affecting others. In this review, we summarize the state of the art in our understanding of the differences between the dopaminergic neurons of the VTA and the SNpc, such as anatomy, structure, morphology, output and input, electrophysiology, development, and disorders, and discuss the current technologies and methods available for studying these two classes of dopaminergic neurons, highlighting their advantages, limitations, and the necessary improvements required to achieve more-precise therapeutic interventions.
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Affiliation(s)
- Valentina Basso
- School of Medicine, Keele University, Staffordshire ST5 5BG, UK
| | - Máté D Döbrössy
- Laboratory of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional, Neurosurgery, Medical Center, University of Freiburg, 79106 Freiburg im Breisgau, Germany
- Department of Stereotactic and Functional Neurosurgery, Medical Center, University of Freiburg, 79106 Freiburg im Breisgau, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg im Breisgau, Germany
| | - Lachlan H Thompson
- Charles Perkins Centre, Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Deniz Kirik
- Brain Repair and Imaging in Neural Systems (B.R.A.I.N.S) Unit, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden
| | - Heidi R Fuller
- School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5 5BG, UK
- Wolfson Centre for Inherited Neuromuscular Disease, TORCH Building, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK
| | - Monte A Gates
- School of Medicine, Keele University, Staffordshire ST5 5BG, UK
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7
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Jothi D, Kulka LAM. Strategies for modeling aging and age-related diseases. NPJ AGING 2024; 10:32. [PMID: 38987252 PMCID: PMC11237002 DOI: 10.1038/s41514-024-00161-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 06/18/2024] [Indexed: 07/12/2024]
Abstract
The ability to reprogram patient-derived-somatic cells to IPSCs (Induced Pluripotent Stem Cells) has led to a better understanding of aging and age-related diseases like Parkinson's, and Alzheimer's. The established patient-derived disease models mimic disease pathology and can be used to design drugs for aging and age-related diseases. However, the age and genetic mutations of the donor cells, the employed reprogramming, and the differentiation protocol might often pose challenges in establishing an appropriate disease model. In this review, we will focus on the various strategies for the successful reprogramming and differentiation of patient-derived cells to disease models for aging and age-related diseases, emphasizing the accuracy in the recapitulation of disease pathology and ways to overcome the limitations of its potential application in cell replacement therapy and drug development.
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Affiliation(s)
- D Jothi
- Department of Biochemistry II, Friedrich Schiller University, Jena, Germany.
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Pazzin DB, Previato TTR, Budelon Gonçalves JI, Zanirati G, Xavier FAC, da Costa JC, Marinowic DR. Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies. Cells 2024; 13:745. [PMID: 38727281 PMCID: PMC11083827 DOI: 10.3390/cells13090745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/19/2024] [Accepted: 03/19/2024] [Indexed: 05/13/2024] Open
Abstract
This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.
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Affiliation(s)
- Douglas Bottega Pazzin
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil; (D.B.P.); (T.T.R.P.); (J.I.B.G.); (G.Z.); (F.A.C.X.); (J.C.d.C.)
- Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90619-900, Brazil
| | - Thales Thor Ramos Previato
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil; (D.B.P.); (T.T.R.P.); (J.I.B.G.); (G.Z.); (F.A.C.X.); (J.C.d.C.)
- Graduate Program in Biomedical Gerontology, School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90619-900, Brazil
| | - João Ismael Budelon Gonçalves
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil; (D.B.P.); (T.T.R.P.); (J.I.B.G.); (G.Z.); (F.A.C.X.); (J.C.d.C.)
| | - Gabriele Zanirati
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil; (D.B.P.); (T.T.R.P.); (J.I.B.G.); (G.Z.); (F.A.C.X.); (J.C.d.C.)
| | - Fernando Antonio Costa Xavier
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil; (D.B.P.); (T.T.R.P.); (J.I.B.G.); (G.Z.); (F.A.C.X.); (J.C.d.C.)
| | - Jaderson Costa da Costa
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil; (D.B.P.); (T.T.R.P.); (J.I.B.G.); (G.Z.); (F.A.C.X.); (J.C.d.C.)
| | - Daniel Rodrigo Marinowic
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil; (D.B.P.); (T.T.R.P.); (J.I.B.G.); (G.Z.); (F.A.C.X.); (J.C.d.C.)
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Barnhoorn S, Milanese C, Li T, Dons L, Ghazvini M, Sette M, Farina S, Sproviero D, Payan-Gomez C, Mastroberardino PG. Orthogonal analysis of mitochondrial function in Parkinson's disease patients. Cell Death Dis 2024; 15:243. [PMID: 38570521 PMCID: PMC10991487 DOI: 10.1038/s41419-024-06617-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 04/05/2024]
Abstract
The etiopathology of Parkinson's disease has been associated with mitochondrial defects at genetic, laboratory, epidemiological, and clinical levels. These converging lines of evidence suggest that mitochondrial defects are systemic and causative factors in the pathophysiology of PD, rather than being mere correlates. Understanding mitochondrial biology in PD at a granular level is therefore crucial from both basic science and translational perspectives. In a recent study, we investigated mitochondrial alterations in fibroblasts obtained from PD patients assessing mitochondrial function in relation to clinical measures. Our findings demonstrated that the magnitude of mitochondrial alterations parallels disease severity. In this study, we extend these investigations to blood cells and dopamine neurons derived from induced pluripotent stem cells reprogrammed from PD patients. To overcome the inherent metabolic heterogeneity of blood cells, we focused our analyses on metabolically homogeneous, accessible, and expandable erythroblasts. Our results confirm the presence of mitochondrial anomalies in erythroblasts and induced dopamine neurons. Consistent with our previous findings in fibroblasts, we observed that mitochondrial alterations are reversible, as evidenced by enhanced mitochondrial respiration when PD erythroblasts were cultured in a galactose medium that restricts glycolysis. This observation indicates that suppression of mitochondrial respiration may constitute a protective, adaptive response in PD pathogenesis. Notably, this effect was not observed in induced dopamine neurons, suggesting their distinct bioenergetic behavior. In summary, we provide additional evidence for the involvement of mitochondria in the disease process by demonstrating mitochondrial abnormalities in additional cell types relevant to PD. These findings contribute to our understanding of PD pathophysiology and may have implications for the development of novel biomarkers and therapeutic strategies.
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Affiliation(s)
- Sander Barnhoorn
- Department of Molecular Genetics, Erasmus MC, Rotterdam, Netherlands
| | - Chiara Milanese
- IFOM-ETS, the AIRC Institute for molecular Oncology, Milan, Italy
| | - Tracy Li
- Erasmus MC iPS Facility, Erasmus MC, Rotterdam, Netherlands
| | - Lieke Dons
- Erasmus MC iPS Facility, Erasmus MC, Rotterdam, Netherlands
| | | | | | - Stefania Farina
- Department of Molecular Genetics, Erasmus MC, Rotterdam, Netherlands
| | - Daisy Sproviero
- IFOM-ETS, the AIRC Institute for molecular Oncology, Milan, Italy
| | | | - Pier G Mastroberardino
- Department of Molecular Genetics, Erasmus MC, Rotterdam, Netherlands.
- IFOM-ETS, the AIRC Institute for molecular Oncology, Milan, Italy.
- Università degli Studi dell'Aquila, L'Aquila, Italy.
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Suzuki H, Egawa N, Imamura K, Kondo T, Enami T, Tsukita K, Suga M, Yada Y, Shibukawa R, Takahashi R, Inoue H. Mutant α-synuclein causes death of human cortical neurons via ERK1/2 and JNK activation. Mol Brain 2024; 17:14. [PMID: 38444039 PMCID: PMC10916047 DOI: 10.1186/s13041-024-01086-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/26/2024] [Indexed: 03/07/2024] Open
Abstract
Synucleinopathies refer to a group of disorders characterized by SNCA/α-synuclein (α-Syn)-containing cytoplasmic inclusions and neuronal cell loss in the nervous system including the cortex, a common feature being cognitive impairment. Still, the molecular pathogenesis of cognitive decline remains poorly understood, hampering the development of effective treatments. Here, we generated induced pluripotent stem cells (iPSCs) derived from familial Parkinson's disease (PD) patients carrying SNCA A53T mutation, differentiating them into cortical neurons by a direct conversion method. Patient iPSCs-derived cortical neurons harboring mutant α-Syn exhibited increased α-Syn-positive aggregates, shorter neurites, and time-dependent vulnerability. Furthermore, RNA-sequencing analysis, followed by biochemical validation, identified the activation of the ERK1/2 and JNK cascades in cortical neurons with SNCA A53T mutation. This result was consistent with a reverted phenotype of neuronal death in cortical neurons when treated with ERK1/2 and JNK inhibitors, respectively. Our findings emphasize the role of ERK1/2 and JNK cascades in the vulnerability of cortical neurons in synucleinopathies, and they could pave the way toward therapeutic advancements for synucleinopathies.
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Affiliation(s)
- Hidefumi Suzuki
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Naohiro Egawa
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Keiko Imamura
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
- Medical-Risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan
| | - Takayuki Kondo
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
- Medical-Risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan
| | - Takako Enami
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
- Medical-Risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan
| | - Kayoko Tsukita
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Mika Suga
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Yuichiro Yada
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Ran Shibukawa
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan
| | - Ryosuke Takahashi
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Haruhisa Inoue
- iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan.
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
- Medical-Risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan.
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11
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Pitrez PR, Monteiro LM, Borgogno O, Nissan X, Mertens J, Ferreira L. Cellular reprogramming as a tool to model human aging in a dish. Nat Commun 2024; 15:1816. [PMID: 38418829 PMCID: PMC10902382 DOI: 10.1038/s41467-024-46004-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/12/2024] [Indexed: 03/02/2024] Open
Abstract
The design of human model systems is highly relevant to unveil the underlying mechanisms of aging and to provide insights on potential interventions to extend human health and life span. In this perspective, we explore the potential of 2D or 3D culture models comprising human induced pluripotent stem cells and transdifferentiated cells obtained from aged or age-related disorder-affected donors to enhance our understanding of human aging and to catalyze the discovery of anti-aging interventions.
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Affiliation(s)
- Patricia R Pitrez
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
| | - Luis M Monteiro
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal
- IIIUC-institute of Interdisciplinary Research, University of Coimbra, Casa Costa Alemão, Coimbra, 3030-789, Portugal
| | - Oliver Borgogno
- Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Xavier Nissan
- CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic diseases, Evry cedex, France
| | - Jerome Mertens
- Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
| | - Lino Ferreira
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
- Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal.
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12
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Kaur S, Sharma N, Kumar V, Sharma D, Devi B, Kapil L, Singh C, Singh A. The Role of Mitophagy in Various Neurological Diseases as a Therapeutic Approach. Cell Mol Neurobiol 2023; 43:1849-1865. [PMID: 36326951 PMCID: PMC11412177 DOI: 10.1007/s10571-022-01302-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/05/2022]
Abstract
Mitochondria are critical to multiple cellular processes, from the production of adenosine triphosphate (ATP), maintenance of calcium homeostasis, synthesis of key metabolites, and production of reactive oxygen species (ROS) to maintain necrosis, apoptosis, and autophagy. Therefore, proper clearance and regulation are essential to maintain various physiological processes carried out by the cellular mechanism, including mitophagy and autophagy, by breaking down the damaged intracellular connections under the influence of various genes and proteins and protecting against various neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), and Huntington disease (HD). In this review, we will discuss the role of autophagy, selective macroautophagy, or mitophagy, and its role in neurodegenerative diseases along with normal physiology. In addition, this review will provide a better understanding of the pathways involved in neuron autophagy and mitophagy and how mutations affect these pathways in the various genes involved in neurodegenerative diseases. Various new findings indicate that the pathways that remove dysfunctional mitochondria are impaired in these diseases, leading to the deposition of damaged mitochondria. Apart from that, we have also discussed the therapeutic strategies targeting autophagy and mitophagy in neurodegenerative diseases. The mitophagy cycle results in the degradation of damaged mitochondria and the biogenesis of new healthy mitochondria, also highlighting different stages at which a particular neurodegenerative disease could occur.
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Affiliation(s)
- Simranjit Kaur
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Neelam Sharma
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Vishal Kumar
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Deepali Sharma
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Bhawna Devi
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Lakshay Kapil
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Charan Singh
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Arti Singh
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India.
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India.
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13
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Chen J, Huang L, Yang Y, Xu W, Qin Q, Qin R, Liang X, Lai X, Huang X, Xie M, Chen L. Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges. Brain Sci 2023; 13:brainsci13030524. [PMID: 36979334 PMCID: PMC10046178 DOI: 10.3390/brainsci13030524] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Nervous system diseases present significant challenges to the neuroscience community due to ethical and practical constraints that limit access to appropriate research materials. Somatic cell reprogramming has been proposed as a novel way to obtain neurons. Various emerging techniques have been used to reprogram mature and differentiated cells into neurons. This review provides an overview of somatic cell reprogramming for neurological research and therapy, focusing on neural reprogramming and generating different neural cell types. We examine the mechanisms involved in reprogramming and the challenges that arise. We herein summarize cell reprogramming strategies to generate neurons, including transcription factors, small molecules, and microRNAs, with a focus on different types of cells.. While reprogramming somatic cells into neurons holds the potential for understanding neurological diseases and developing therapeutic applications, its limitations and risks must be carefully considered. Here, we highlight the potential benefits of somatic cell reprogramming for neurological disease research and therapy. This review contributes to the field by providing a comprehensive overview of the various techniques used to generate neurons by cellular reprogramming and discussing their potential applications.
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Affiliation(s)
- Jiafeng Chen
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Lijuan Huang
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Yue Yang
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Wei Xu
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Qingchun Qin
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Rongxing Qin
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Xiaojun Liang
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Xinyu Lai
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Nanning 530021, China
| | - Xiaoying Huang
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Minshan Xie
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Li Chen
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Nanning 530021, China
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14
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Sharma N, Banerjee R, Davis RL. Early Mitochondrial Defects in the 5xFAD Mouse Model of Alzheimer's Disease. J Alzheimers Dis 2023; 91:1323-1338. [PMID: 36617782 DOI: 10.3233/jad-220884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Mitochondrial (MT) dysfunction is a hallmark of Alzheimer's disease (AD). Amyloid-β protein precursor and amyloid-β peptides localize to MT and lead to MT dysfunction in familial forms of AD. This dysfunction may trigger subsequent types of pathology. OBJECTIVE To identify the MT phenotypes that occur early in order to help understand the cascade of AD pathophysiology. METHODS The 5xFAD mouse model was used to explore the time course of MT pathologies in both sexes. Protein biomarkers for MT dynamics were measured biochemically and MT function was measured using oxygen consumption and ATP assays. RESULTS We discovered progressive alterations in mitochondrial dynamics (biogenesis, fission, fusion, and mitophagy) and function (O2 consumption, ATP generation, and Ca2+ import) in the hippocampus of 5xFAD mice in both sexes as early as 2 months of age. Thus, mitochondrial dynamics and function become altered at young ages, consistent with an early role for mitochondria in the AD pathological cascade. CONCLUSION Our study offers the baseline information required to understand the hierarchical relationship between the multiple pathologies that develop in this mouse model and provides early biomarkers for MT dysfunction. This will aid in dissecting the temporal cascade of pathologies, understanding sex-specific differences, and in testing the efficacy of putative mitochondrial therapeutics.
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Affiliation(s)
- Neelam Sharma
- Department of Neuroscience, University of Florida Scripps Biomedical Research Institute, Jupiter, FL, USA
| | - Rupkatha Banerjee
- Department of Neuroscience, University of Florida Scripps Biomedical Research Institute, Jupiter, FL, USA
| | - Ronald L Davis
- Department of Neuroscience, University of Florida Scripps Biomedical Research Institute, Jupiter, FL, USA
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15
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Aversano S, Caiazza C, Caiazzo M. Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures. Front Aging Neurosci 2022; 14:1069482. [PMID: 36620769 PMCID: PMC9810544 DOI: 10.3389/fnagi.2022.1069482] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 11/22/2022] [Indexed: 12/24/2022] Open
Abstract
Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models.
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Affiliation(s)
- Simona Aversano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Carmen Caiazza
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Massimiliano Caiazzo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy,Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, Netherlands,*Correspondence: Massimiliano Caiazzo,
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16
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Schwarz L, Sharma K, Dodi LD, Rieder LS, Fallier-Becker P, Casadei N, Fitzgerald JC. Miro1 R272Q disrupts mitochondrial calcium handling and neurotransmitter uptake in dopaminergic neurons. Front Mol Neurosci 2022; 15:966209. [PMID: 36533136 PMCID: PMC9757607 DOI: 10.3389/fnmol.2022.966209] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 11/11/2022] [Indexed: 11/07/2023] Open
Abstract
The Rho GTPase Miro1, located at the mitochondrial outer membrane is known to properly distribute mitochondria to synapses, aid calcium buffering and initiate PINK1-Parkin mediated mitophagy. Several heterozygous RHOT1/Miro1 variants were identified in sporadic Parkinson's disease patients. Miro1 R272Q is located within a calcium binding domain, but the functional outcome of this point mutation and its contribution to the development of disease are unclear. To address this, we introduced a heterozygous RHOT1/Miro1 R272Q point mutation in healthy induced pluripotent stem cells. In dopaminergic neurons, Miro1 R272Q does not affect Miro1 protein levels, CCCP-induced mitophagy, nor mitochondrial movement yet causes the fragmentation of mitochondria with reduction of cristae and ATP5A. Inhibition of the mitochondrial calcium uniporter phenocopied Miro1 R272Q cytosolic calcium response to Thapsigargin in active neurons, a similar effect was observed during the calcium buffering phase in Miro1 knockdown neuroblastoma cells. Altered mitochondrial calcium regulation is associated with reduced mitochondrial respiration and reduced catecholamine neurotransmitter uptake. Synaptic changes are not coupled to dopamine distribution or dopamine transporters but are linked to Miro1 R272Q-related calcium handling via the mitochondria concomitant with defective dopamine regulation at the mitochondrial surface by monoamine oxidase. We conclude that the Miro1 R272Q heterozygous point mutation dampens mitochondrial-calcium regulation and mitochondrial capacity via events at the outer membrane that are sufficient to disrupt dopaminergic function.
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Affiliation(s)
- Lisa Schwarz
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Karan Sharma
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Lorenzo D Dodi
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Lara-Sophie Rieder
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Petra Fallier-Becker
- Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany
| | - Nicolas Casadei
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- NGS Competence Center Tübingen, Tübingen, Germany
| | - Julia C Fitzgerald
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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17
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Erekat NS. Autophagy and Its Association with Genetic Mutations in Parkinson Disease. Med Sci Monit 2022; 28:e938519. [PMID: 36366737 PMCID: PMC9664771 DOI: 10.12659/msm.938519] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 10/19/2022] [Indexed: 08/07/2023] Open
Abstract
Parkinson disease is the second most common neurodegenerative disorder, affecting 0.1-0.2% of the general population. It is a progressive debilitating disorder caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta. It is characterized by motor and non-motor symptoms. Parkinson disease can be caused by mutations in genes that encode proteins involved in the autophagic process, resulting in impaired autophagy. Indeed, autophagy has been implicated in the pathogenesis of Parkinson disease, particularly because its impairment causes the buildup of proteins. Thus, this review aims to provide an overview of Parkinson disease-related genetic mutations and their association with autophagy impairment in Parkinson disease, which can be helpful in improving the understanding of the pathogenesis of Parkinson disease, illustrating the potential therapeutic implications of agents that can enhance autophagy in Parkinson disease. Additionally, we will highlight the essential need for the development of highly sensitive and specific assays for gene-based diagnostic biomarkers. Finally, we will provide an overview on the potential gene-based therapeutic approaches for Parkinson disease, which have been most advanced and are associated with the most common targets being alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2), and glucocerebrosidase (GBA).
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18
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Kim J, Daadi EW, Oh T, Daadi ES, Daadi MM. Human Induced Pluripotent Stem Cell Phenotyping and Preclinical Modeling of Familial Parkinson's Disease. Genes (Basel) 2022; 13:1937. [PMID: 36360174 PMCID: PMC9689743 DOI: 10.3390/genes13111937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/13/2022] [Accepted: 10/18/2022] [Indexed: 12/05/2022] Open
Abstract
Parkinson's disease (PD) is primarily idiopathic and a highly heterogenous neurodegenerative disease with patients experiencing a wide array of motor and non-motor symptoms. A major challenge for understanding susceptibility to PD is to determine the genetic and environmental factors that influence the mechanisms underlying the variations in disease-associated traits. The pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the brain and post-mortem Lewy pathology, which leads to the loss of projecting axons innervating the striatum and to impaired motor and cognitive functions. While the cause of PD is still largely unknown, genome-wide association studies provide evidence that numerous polymorphic variants in various genes contribute to sporadic PD, and 10 to 15% of all cases are linked to some form of hereditary mutations, either autosomal dominant or recessive. Among the most common mutations observed in PD patients are in the genes LRRK2, SNCA, GBA1, PINK1, PRKN, and PARK7/DJ-1. In this review, we cover these PD-related mutations, the use of induced pluripotent stem cells as a disease in a dish model, and genetic animal models to better understand the diversity in the pathogenesis and long-term outcomes seen in PD patients.
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Affiliation(s)
- Jeffrey Kim
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
- Cell Systems and Anatomy, San Antonio, TX 78229, USA
| | - Etienne W. Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Thomas Oh
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Elyas S. Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Marcel M. Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
- Cell Systems and Anatomy, San Antonio, TX 78229, USA
- Department of Radiology, Long School of Medicine, University of Texas Health at San Antonio, San Antonio, TX 78229, USA
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19
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Xiao B, Kuruvilla J, Tan EK. Mitophagy and reactive oxygen species interplay in Parkinson's disease. NPJ Parkinsons Dis 2022; 8:135. [PMID: 36257956 PMCID: PMC9579202 DOI: 10.1038/s41531-022-00402-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 09/28/2022] [Indexed: 11/08/2022] Open
Abstract
Mitophagy impairment and oxidative stress are cardinal pathological hallmarks in Parkinson's disease (PD), a common age-related neurodegenerative condition. The specific interactions between mitophagy and reactive oxygen species (ROS) have attracted considerable attention even though their exact interplay in PD has not been fully elucidated. We highlight the interactions between ROS and mitophagy, with a focus on the signalling pathways downstream to ROS that triggers mitophagy and draw attention to potential therapeutic compounds that target these pathways in both experimental and clinical models. Identifying a combination of ROS inhibitors and mitophagy activators to provide a physiologic balance in this complex signalling pathways may lead to a more optimal outcome. Deciphering the exact temporal relationship between mitophagy and oxidative stress and their triggers early in the course of neurodegeneration can unravel mechanistic clues that potentially lead to the development of compounds for clinical drug trials focusing on prodromic PD or at-risk individuals.
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Affiliation(s)
- Bin Xiao
- Department of Neurology, National Neuroscience Institute, Singapore, Singapore.
- Neuroscience Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore.
| | - Joshua Kuruvilla
- Department of Neurology, National Neuroscience Institute, Singapore, Singapore
| | - Eng-King Tan
- Department of Neurology, National Neuroscience Institute, Singapore, Singapore.
- Neuroscience Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore.
- Neuroscience and Behavioral Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
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20
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Rai P, Kumar Roy J. Endosomal recycling protein Rab11 in Parkin and Pink1 signaling in Drosophila model of Parkinson's disease. Exp Cell Res 2022; 420:113357. [PMID: 36116557 DOI: 10.1016/j.yexcr.2022.113357] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/23/2022] [Accepted: 09/11/2022] [Indexed: 11/16/2022]
Abstract
Neurodegenerative diseases are progressive disorders of the nervous system primarily affecting the loss of neuronal cells present in the brain. Although most neurodegenerative cases are sporadic, some familial genes are found to be involved in the neurodegenerative diseases. The extensively studied parkin and pink1 gene products are known to be involved in the removal of damaged mitochondria via autophagy (mitophagy), a quality control process. If the function of any of these genes is somehow disrupted, accumulation of damaged mitochondria occurs in the forms of protein aggregates in the cytoplasm, leading to formation of the Lewy-bodies. Autophagy is an important catabolic process where the endosomal Rab proteins are seen to be involved. Rab11, an endosomal recycling protein, serves as an ATG9A carrier that helps in autophagosome formation and maturation. Earlier studies have reported that loss of Rab11 prevents the fusion of autophagosomes with the late endosomes hampering the autophagy pathway resulting in apoptosis of cells. In this study, we have emphasized on the importance and functional role of Rab11 in the molecular pathway of Parkin/Pink1 in Parkinson's disease.
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Affiliation(s)
- Pooja Rai
- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
| | - Jagat Kumar Roy
- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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21
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Inagaki E, Yoshimatsu S, Okano H. Accelerated neuronal aging in vitro ∼melting watch ∼. Front Aging Neurosci 2022; 14:868770. [PMID: 36016855 PMCID: PMC9397486 DOI: 10.3389/fnagi.2022.868770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
In developed countries, the aging of the population and the associated increase in age-related diseases are causing major unresolved medical, social, and environmental matters. Therefore, research on aging has become one of the most important and urgent issues in life sciences. If the molecular mechanisms of the onset and progression of neurodegenerative diseases are elucidated, we can expect to develop disease-modifying methods to prevent neurodegeneration itself. Since the discovery of induced pluripotent stem cells (iPSCs), there has been an explosion of disease models using disease-specific iPSCs derived from patient-derived somatic cells. By inducing the differentiation of iPSCs into neurons, disease models that reflect the patient-derived pathology can be reproduced in culture dishes, and are playing an active role in elucidating new pathological mechanisms and as a platform for new drug discovery. At the same time, however, we are faced with a new problem: how to recapitulate aging in culture dishes. It has been pointed out that cells differentiated from pluripotent stem cells are juvenile, retain embryonic traits, and may not be fully mature. Therefore, attempts are being made to induce cell maturation, senescence, and stress signals through culture conditions. It has also been reported that direct conversion of fibroblasts into neurons can reproduce human neurons with an aged phenotype. Here, we outline some state-of-the-art insights into models of neuronal aging in vitro. New frontiers in which stem cells and methods for inducing differentiation of tissue regeneration can be applied to aging research are just now approaching, and we need to keep a close eye on them. These models are forefront and intended to advance our knowledge of the molecular mechanisms of aging and contribute to the development of novel therapies for human neurodegenerative diseases associated with aging.
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Affiliation(s)
- Emi Inagaki
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
- Japanese Society for the Promotion of Science (JSPS), Tokyo, Japan
| | - Sho Yoshimatsu
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
- *Correspondence: Hideyuki Okano,
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22
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Bose A, Petsko GA, Studer L. Induced pluripotent stem cells: a tool for modeling Parkinson's disease. Trends Neurosci 2022; 45:608-620. [PMID: 35667922 PMCID: PMC9576003 DOI: 10.1016/j.tins.2022.05.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 04/04/2022] [Accepted: 05/09/2022] [Indexed: 12/26/2022]
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Among its pathologies, progressive loss of dopaminergic (DA) neurons in the substantia nigra is characteristic and contributes to many of the most severe symptoms of PD. Recent advances in induced pluripotent stem cell (iPSC) technology have made it possible to generate patient-derived DA neuronal cell culture and organoid models of PD. These models have contributed to understanding disease mechanisms and the identification of novel targets and therapeutic candidates. Still needed are better ways to model the age-related aspects of PD, as well as a deeper understanding of the interactions among disease-modifying genes and between genetic and environmental contributions to the etiology and progression of PD.
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Affiliation(s)
- Anindita Bose
- Ann Romney Institute of Neurological Diseases, Harvard Medical School/Brigham and Women's Hospital, Boston, MA, USA; The Center for Stem Cell Biology, Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
| | - Gregory A Petsko
- Ann Romney Institute of Neurological Diseases, Harvard Medical School/Brigham and Women's Hospital, Boston, MA, USA; The Center for Stem Cell Biology, Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA
| | - Lorenz Studer
- The Center for Stem Cell Biology, Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA
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23
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Burtscher J, Romani M, Bernardo G, Popa T, Ziviani E, Hummel FC, Sorrentino V, Millet GP. Boosting mitochondrial health to counteract neurodegeneration. Prog Neurobiol 2022; 215:102289. [DOI: 10.1016/j.pneurobio.2022.102289] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/23/2022] [Accepted: 05/25/2022] [Indexed: 12/22/2022]
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24
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Eldeeb MA, Thomas RA, Ragheb MA, Fallahi A, Fon EA. Mitochondrial quality control in health and in Parkinson's disease. Physiol Rev 2022; 102:1721-1755. [PMID: 35466694 DOI: 10.1152/physrev.00041.2021] [Citation(s) in RCA: 132] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
As a central hub for cellular metabolism and intracellular signalling, the mitochondrion is a pivotal organelle, dysfunction of which has been linked to several human diseases including neurodegenerative disorders, and in particular Parkinson's disease. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to monitor, identify, repair and/or eliminate abnormal or misfolded proteins within the mitochondrion and/or the dysfunctional mitochondrion itself. Chaperones identify unstable or otherwise abnormal conformations in mitochondrial proteins and can promote their refolding to recover their correct conformation and stability. However, if repair is not possible, the abnormal protein is selectively degraded to prevent potentially damaging interactions with other proteins or its oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of such abnormal or misfolded protein species. Mitophagy (a specific kind of autophagy) mediates the selective elimination of dysfunctional mitochondria, in order to prevent the deleterious effects the dysfunctional organelles within the cell. Despite our increasing understanding of the molecular responses toward dysfunctional mitochondria, many key aspects remain relatively poorly understood. Herein, we review the emerging mechanisms of mitochondrial quality control including quality control strategies coupled to mitochondrial import mechanisms. In addition, we review the molecular mechanisms regulating mitophagy with an emphasis on the regulation of PINK1/PARKIN-mediated mitophagy in cellular physiology and in the context of Parkinson's disease cell biology.
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Affiliation(s)
- Mohamed A Eldeeb
- McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Rhalena A Thomas
- McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Mohamed A Ragheb
- Chemistry Department (Biochemistry Division), Faculty of Science, Cairo University, Giza, Egypt
| | - Armaan Fallahi
- McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Edward A Fon
- McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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Wasner K, Smajic S, Ghelfi J, Delcambre S, Prada-Medina CA, Knappe E, Arena G, Mulica P, Agyeah G, Rakovic A, Boussaad I, Badanjak K, Ohnmacht J, Gérardy JJ, Takanashi M, Trinh J, Mittelbronn M, Hattori N, Klein C, Antony P, Seibler P, Spielmann M, Pereira SL, Grünewald A. Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation. Mov Disord 2022; 37:1405-1415. [PMID: 35460111 DOI: 10.1002/mds.29025] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/07/2022] [Accepted: 03/27/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient-derived neurons. OBJECTIVES We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level. METHODS We generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single-nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)-treated iPSC-derived neuron-microglia co-cultures. RESULTS Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin-deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin-deficient neuron-microglia co-cultures elicited an enhanced immune response when exposed to mtDNA/LPS. CONCLUSIONS Our findings suggest that parkin coregulates mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby protecting midbrain neurons from neuroinflammation and degeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Kobi Wasner
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette
| | - Semra Smajic
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette
| | - Jenny Ghelfi
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette
| | - Sylvie Delcambre
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette
| | | | - Evelyn Knappe
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Giuseppe Arena
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette
| | - Patrycja Mulica
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette
| | - Gideon Agyeah
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette
| | | | - Ibrahim Boussaad
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette.,Disease Modeling and Screening Platform, Luxembourg Centre of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, Luxembourg
| | - Katja Badanjak
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette
| | - Jochen Ohnmacht
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette.,Department of Life Science and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Jean-Jacques Gérardy
- National Center of Pathology, Laboratoire National de Santé, Dudelange, Luxembourg
| | | | - Joanne Trinh
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Michel Mittelbronn
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette.,National Center of Pathology, Laboratoire National de Santé, Dudelange, Luxembourg.,Luxembourg Center of Neuropathology, Dudelange, Luxembourg.,Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | | | - Christine Klein
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Paul Antony
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette.,Disease Modeling and Screening Platform, Luxembourg Centre of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, Luxembourg
| | - Philip Seibler
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Malte Spielmann
- Max Planck Institute for Molecular Genetics, Berlin, Germany.,Institute of Human Genetics, University of Lübeck, Lübeck, Germany
| | - Sandro L Pereira
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette.,Department of Neurology, Juntendo University, Tokyo, Japan
| | - Anne Grünewald
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette.,Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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26
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Hou PS, Kuo HC. Central nervous system organoids for modeling neurodegenerative diseases. IUBMB Life 2022; 74:812-825. [PMID: 35102668 DOI: 10.1002/iub.2595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/18/2021] [Accepted: 12/02/2021] [Indexed: 11/07/2022]
Abstract
Recent advances in induced pluripotent stem cell (iPSC) technology have allowed researchers to generate neurodegenerative disease-specific iPSCs and use the cells to derive a variety of relevant cell populations for laboratory modeling and drug testing. Nevertheless, these efforts have faced challenges related to immaturity and lack of complex developmental niches in the derived cell populations, limiting the utility of these in vitro models of neurodegenerative disease. Such limitations may be overcome by using human iPSC technology to generate three-dimensional (3D) brain organoids, which better recapitulate in vivo tissue architecture than traditional neuronal cultures to provide more complex and representative disease models and drug testing systems. In this review, we focus on the application of pluripotent stem cell-derived central nervous system (CNS) organoids to model neurodegenerative diseases. We first summarize recent progress in generating and characterizing various CNS organoids from pluripotent stem cells. We then review the application of CNS organoids for modeling several different human neurodegenerative diseases. We also describe several novel pathological mechanisms and drugs that were studied using patient iPSC-derived CNS organoids. Finally, we discuss remaining challenges and emerging opportunities for the use of 3D brain organoids for in vitro modeling of CNS development and neurodegeneration.
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Affiliation(s)
- Pei-Shan Hou
- Institute of Anatomy and Cell Biology, National Yang-Ming Chiao-Tung University, Taipei, Taiwan.,Brain Research Center, National Yang-Ming Chiao-Tung University, Taipei, Taiwan
| | - Hung-Chih Kuo
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.,Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
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27
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Grekhnev DA, Kaznacheyeva EV, Vigont VA. Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling. Int J Mol Sci 2022; 23:624. [PMID: 35054808 PMCID: PMC8776084 DOI: 10.3390/ijms23020624] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 02/04/2023] Open
Abstract
The development of cell reprogramming technologies became a breakthrough in the creation of new models of human diseases, including neurodegenerative pathologies. The iPSCs-based models allow for the studying of both hereditary and sporadic cases of pathologies and produce deep insight into the molecular mechanisms underlying neurodegeneration. The use of the cells most vulnerable to a particular pathology makes it possible to identify specific pathological mechanisms and greatly facilitates the task of selecting the most effective drugs. To date, a large number of studies on patient-specific models of neurodegenerative diseases has been accumulated. In this review, we focused on the alterations of such a ubiquitous and important intracellular regulatory pathway as calcium signaling. Here, we reviewed and analyzed the data obtained from iPSCs-based models of different neurodegenerative disorders that demonstrated aberrant calcium signaling.
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Affiliation(s)
| | | | - Vladimir A. Vigont
- Laboratory of Ionic Channels of Cell Membranes, Department of Molecular Physiology of the Cell, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Ave., 194064 St. Petersburg, Russia; (D.A.G.); (E.V.K.)
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28
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Chmiela T, Węgrzynek J, Kasprzyk A, Waksmundzki D, Wilczek D, Gorzkowska A. If Not Insulin Resistance so What? - Comparison of Fasting Glycemia in Idiopathic Parkinson's Disease and Atypical Parkinsonism. Diabetes Metab Syndr Obes 2022; 15:1451-1460. [PMID: 35586204 PMCID: PMC9109887 DOI: 10.2147/dmso.s359856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/29/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Parkinson's disease (PD) is a synucleinopathy, which presents dysautonomia, as its common non-motor symptom. Some research suggests the existing interplay between the autonomic nervous system dysfunction and glucose metabolism dysregulation in PD. OBJECTIVE To determine the prevalence of metabolic disorders with particular emphasis on glucose metabolism in patients with PD and atypical parkinsonism (AP). PATIENTS AND METHODS A retrospective study was performed by analyzing 461 clinical data of consecutive patients diagnosed with PD, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) hospitalized from 2019 to 2021 in the authors' institution. The study group included 350 patients (303 PD, 14 MSA, 33 PSP), aged 65.8 ± 9.7 years (42% were female). Laboratory results (fasting glycemia, lipid parameters, TSH, homocysteine and vitamin D3 levels) were collected. The patient's clinical condition was assessed in III part of Unified Parkinson's Disease Rating Scale (UPDRS p. III), Hoehn-Yahr scale, Mini Mental State Examination (MMSE) and Beck Depression Inventory (BDI). RESULTS Impaired fasting glycemia (IGF) was more prevalent in PD than in the PSP (43.43% vs 18.18%; p = 0.043). Similarly, PD presented a higher level of fasting glycemia (102.4 ± 16.7 mg/dl vs 92.2 ± 16.1mg/dl; p = 0.042). According to lipid parameters, patients with PD showed lower LDL cholesterol (92.3 ± 44.3mg/dl vs 119 ± 61.0mg/dl; p = 0.016) and lower BMI compared to patients with PSP (26.1 ± 4.0kg/m2 vs 29.3 ± 4.4 kg/m2; p = 0.024), but there were no statistically significant differences in triglycerides (TG) and HDL cholesterol levels. Males with PD presented greater frequency of IFG (35.05% vs 50.6%; p = 0.042), higher fasting glycemia (99.1 ± 14.3mg/dl vs 103.7 ± 14.7mg/dl; p = 0.006), lower total cholesterol, HDL cholesterol, and BMI compared to women with PD. CONCLUSION Our investigation supports an association between synucleinopathies and glucose metabolism dysregulation.
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Affiliation(s)
- Tomasz Chmiela
- Department of Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
- Correspondence: Tomasz Chmiela, Department of Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland, Tel +48 32 789 46 01, Fax +48 32 789 45 55, Email
| | - Julia Węgrzynek
- Students’ Scientific Association, Department of Neurorehabilitation, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Amadeusz Kasprzyk
- Students’ Scientific Association, Department of Neurorehabilitation, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Damian Waksmundzki
- Students’ Scientific Association, Department of Neurorehabilitation, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Dawid Wilczek
- Students’ Scientific Association, Department of Neurorehabilitation, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Agnieszka Gorzkowska
- Department of Neurorehabilitation, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
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29
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Dierolf JG, Watson AJ, Betts DH. 3D Immunofluorescent Image Colocalization Quantification in Mouse Epiblast Stem Cells. Methods Mol Biol 2022; 2490:69-79. [PMID: 35486240 DOI: 10.1007/978-1-0716-2281-0_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
This chapter details 3D morphological topography of colony architecture optimization and nuclear protein localization by co-immunofluorescent confocal microscopy analysis. Colocalization assessment of nuclear and cytoplasmic cell regions is detailed to demonstrate nuclear and cytoplasmic localization in mEpiSCs by confocal microscopy and orthogonal colocalization assessment. Protein colocalization within mESCs, mEpiLCs, and mEpiSCs can be efficiently completed using these optimized protocols.
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Affiliation(s)
- Joshua G Dierolf
- Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
| | - Andrew J Watson
- Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
- Department of Obstetrics and Gynecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
- The Children's Health Research Institute (CHRI), Lawson Health Research Institute, London, ON, Canada
| | - Dean H Betts
- Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada.
- Department of Obstetrics and Gynecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada.
- The Children's Health Research Institute (CHRI), Lawson Health Research Institute, London, ON, Canada.
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30
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Mitochondrial Phenotypes in Parkinson's Diseases-A Focus on Human iPSC-Derived Dopaminergic Neurons. Cells 2021; 10:cells10123436. [PMID: 34943944 PMCID: PMC8699816 DOI: 10.3390/cells10123436] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 12/18/2022] Open
Abstract
Established disease models have helped unravel the mechanistic underpinnings of pathological phenotypes in Parkinson’s disease (PD), the second most common neurodegenerative disorder. However, these discoveries have been limited to relatively simple cellular systems and animal models, which typically manifest with incomplete or imperfect recapitulation of disease phenotypes. The advent of induced pluripotent stem cells (iPSCs) has provided a powerful scientific tool for investigating the underlying molecular mechanisms of both familial and sporadic PD within disease-relevant cell types and patient-specific genetic backgrounds. Overwhelming evidence supports mitochondrial dysfunction as a central feature in PD pathophysiology, and iPSC-based neuronal models have expanded our understanding of mitochondrial dynamics in the development and progression of this devastating disorder. The present review provides a comprehensive assessment of mitochondrial phenotypes reported in iPSC-derived neurons generated from PD patients’ somatic cells, with an emphasis on the role of mitochondrial respiration, morphology, and trafficking, as well as mitophagy and calcium handling in health and disease. Furthermore, we summarize the distinguishing characteristics of vulnerable midbrain dopaminergic neurons in PD and report the unique advantages and challenges of iPSC disease modeling at present, and for future mechanistic and therapeutic applications.
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31
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Mitochondrial Biogenesis in Neurons: How and Where. Int J Mol Sci 2021; 22:ijms222313059. [PMID: 34884861 PMCID: PMC8657637 DOI: 10.3390/ijms222313059] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 11/27/2021] [Accepted: 11/29/2021] [Indexed: 11/27/2022] Open
Abstract
Neurons rely mostly on mitochondria for the production of ATP and Ca2+ homeostasis. As sub-compartmentalized cells, they have different pools of mitochondria in each compartment that are maintained by a constant mitochondrial turnover. It is assumed that most mitochondria are generated in the cell body and then travel to the synapse to exert their functions. Once damaged, mitochondria have to travel back to the cell body for degradation. However, in long cells, like motor neurons, this constant travel back and forth is not an energetically favourable process, thus mitochondrial biogenesis must also occur at the periphery. Ca2+ and ATP levels are the main triggers for mitochondrial biogenesis in the cell body, in a mechanism dependent on the Peroxisome-proliferator-activated γ co-activator-1α-nuclear respiration factors 1 and 2-mitochondrial transcription factor A (PGC-1α-NRF-1/2-TFAM) pathway. However, even though of extreme importance, very little is known about the mechanisms promoting mitochondrial biogenesis away from the cell body. In this review, we bring forward the evoked mechanisms that are at play for mitochondrial biogenesis in the cell body and periphery. Moreover, we postulate that mitochondrial biogenesis may vary locally within the same neuron, and we build upon the hypotheses that, in the periphery, local protein synthesis is responsible for giving all the machinery required for mitochondria to replicate themselves.
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32
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Matt SM. Targeting neurotransmitter-mediated inflammatory mechanisms of psychiatric drugs to mitigate the double burden of multimorbidity and polypharmacy. Brain Behav Immun Health 2021; 18:100353. [PMID: 34647105 PMCID: PMC8495104 DOI: 10.1016/j.bbih.2021.100353] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 09/16/2021] [Accepted: 09/18/2021] [Indexed: 12/12/2022] Open
Abstract
The increased incidence of multimorbidities and polypharmacy is a major concern, particularly in the growing aging population. While polypharmacy can be beneficial, in many cases it can be more harmful than no treatment, especially in individuals suffering from psychiatric disorders, who have elevated risks of multimorbidity and polypharmacy. Age-related chronic inflammation and immunopathologies might contribute to these increased risks in this population, but the optimal clinical management of drug-drug interactions and the neuro-immune mechanisms that are involved warrants further investigation. Given that neurotransmitter systems, which psychiatric medications predominantly act on, can influence the development of inflammation and the regulation of immune function, it is important to better understand these interactions to develop more successful strategies to manage these comorbidities and complicated polypharmacy. I propose that expanding upon research in translationally relevant human in vitro models, in tandem with other preclinical models, is critical to defining the neurotransmitter-mediated mechanisms by which psychiatric drugs alter immune function. This will define more precisely the interactions of psychiatric drugs and other immunomodulatory drugs, used in combination, enabling identification of novel targets to be translated into more efficacious diagnostic, preventive, and therapeutic interventions. This interdisciplinary approach will aid in better precision polypharmacy for combating adverse events associated with multimorbidity and polypharmacy in the future.
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Affiliation(s)
- Stephanie M. Matt
- Drexel University College of Medicine, Department of Pharmacology and Physiology, Philadelphia, PA, USA
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33
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Earley AM, Burbulla LF, Krainc D, Awatramani R. Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons. Sci Rep 2021; 11:22257. [PMID: 34782629 PMCID: PMC8593045 DOI: 10.1038/s41598-021-01366-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 10/26/2021] [Indexed: 12/24/2022] Open
Abstract
During cellular specification, transcription factors orchestrate cellular decisions through gene regulation. By hijacking these transcriptional networks, human pluripotent stem cells (hPSCs) can be specialized into neurons with different molecular identities for the purposes of regenerative medicine and disease modeling. However, molecular fine tuning cell types to match their in vivo counterparts remains a challenge. Directing cell fates often result in blended or incomplete neuron identities. A better understanding of hPSC to neuron gene regulation is needed. Here, we used single cell RNA sequencing to resolve some of these graded molecular identities during human neurogenesis from hPSCs. Differentiation platforms were established to model neural induction from stem cells, and we characterized these differentiated cell types by 10x single cell RNA sequencing. Using single cell trajectory and co-expression analyses, we identified a co-regulated transcription factor module expressing achaete-scute family basic helix-loop-helix transcription factor 1 (ASCL1) and neuronal differentiation 1 (NEUROD1). We then tested the function of these transcription factors in neuron subtype differentiation by gene knockout in a novel human system that reports the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. ASCL1 was identified as a necessary transcription factor for regulating dopaminergic neurotransmitter selection.
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Affiliation(s)
- Aaron M Earley
- Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Lena F Burbulla
- Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Dimitri Krainc
- Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Rajeshwar Awatramani
- Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
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Jarazo J, Barmpa K, Modamio J, Saraiva C, Sabaté-Soler S, Rosety I, Griesbeck A, Skwirblies F, Zaffaroni G, Smits LM, Su J, Arias-Fuenzalida J, Walter J, Gomez-Giro G, Monzel AS, Qing X, Vitali A, Cruciani G, Boussaad I, Brunelli F, Jäger C, Rakovic A, Li W, Yuan L, Berger E, Arena G, Bolognin S, Schmidt R, Schröder C, Antony PMA, Klein C, Krüger R, Seibler P, Schwamborn JC. Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment. Mov Disord 2021; 37:80-94. [PMID: 34637165 PMCID: PMC9291890 DOI: 10.1002/mds.28810] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 12/13/2022] Open
Abstract
Background The etiology of Parkinson's disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the phosphatase and tensin homolog (PTEN)‐induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy are sufficient to cause PD. Objectives We sought to evaluate the difference between controls' and PINK1 patients' derived neurons in their transition from neuroepithelial stem cells to neurons, allowing us to identify potential pathways to target with repurposed compounds. Methods Using two‐dimensional and three‐dimensional models of patients' derived neurons we recapitulated PD‐related phenotypes. We introduced the usage of midbrain organoids for testing compounds. Using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR‐associated protein 9 (Cas9), we corrected the point mutations of three patients' derived cells. We evaluated the effect of the selected compound in a mouse model. Results PD patient‐derived cells presented differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to tyrosine hydroxylase positive (TH+) neurons compared to controls' cells. Correction of a patient's point mutation ameliorated the metabolic properties and neuronal firing rates as well as reversing the differentiation phenotype, and reducing the increased astrocytic levels. Treatment with 2‐hydroxypropyl‐β‐cyclodextrin increased the autophagy and mitophagy capacity of neurons concomitant with an improved dopaminergic differentiation of patient‐specific neurons in midbrain organoids and ameliorated neurotoxicity in a mouse model. Conclusion We show that treatment with a repurposed compound is sufficient for restoring the impaired dopaminergic differentiation of PD patient‐derived cells. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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Affiliation(s)
- Javier Jarazo
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg.,OrganoTherapeutics société à responsabilité limitée simplifiée (SARL-S), Esch-sur-Alzette, Luxembourg
| | - Kyriaki Barmpa
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Jennifer Modamio
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Cláudia Saraiva
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Sònia Sabaté-Soler
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Isabel Rosety
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | | | | | - Gaia Zaffaroni
- Institute for Globally Distributed Open Research and Education, Gothenburg, Sweden
| | - Lisa M Smits
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Jihui Su
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Jonathan Arias-Fuenzalida
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Jonas Walter
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Gemma Gomez-Giro
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Anna S Monzel
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Xiaobing Qing
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Armelle Vitali
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Gerald Cruciani
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg.,Disease Modeling and Screening Platform, Luxembourg Institute of Systems Biomedicine, University of Luxembourg and Luxembourg Institute of Health, Belvaux, Luxembourg
| | - Ibrahim Boussaad
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg.,Disease Modeling and Screening Platform, Luxembourg Institute of Systems Biomedicine, University of Luxembourg and Luxembourg Institute of Health, Belvaux, Luxembourg
| | | | - Christian Jäger
- Metabolomics Platform, Enzymology and Metabolism, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | | | - Wen Li
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Lin Yuan
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Emanuel Berger
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Giuseppe Arena
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Silvia Bolognin
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | | | | | - Paul M A Antony
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Christine Klein
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Rejko Krüger
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg.,Centre Hospitalier de Luxembourg, Parkinson Research Clinic, Luxembourg, Luxembourg.,Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Philip Seibler
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Jens C Schwamborn
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine University of Luxembourg, Esch-sur-Alzette, Luxembourg
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35
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Burbidge K, Rademacher DJ, Mattick J, Zack S, Grillini A, Bousset L, Kwon O, Kubicki K, Simon A, Melki R, Campbell EM. LGALS3 (galectin 3) mediates an unconventional secretion of SNCA/α-synuclein in response to lysosomal membrane damage by the autophagic-lysosomal pathway in human midbrain dopamine neurons. Autophagy 2021; 18:1020-1048. [PMID: 34612142 PMCID: PMC9196737 DOI: 10.1080/15548627.2021.1967615] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Numerous lines of evidence support the premise that the misfolding and subsequent accumulation of SNCA/α-synuclein (synuclein alpha) is responsible for the underlying neuronal pathology observed in Parkinson disease (PD) and other synucleinopathies. Moreover, the cell-to-cell transfer of these misfolded SNCA species is thought to be responsible for disease progression and the spread of cellular pathology throughout the brain. Previous work has shown that when exogenous, misfolded SNCA fibrils enter cells through endocytosis, they can damage and rupture the membranes of their endocytotic vesicles in which they are trafficked. Rupture of these vesicular membranes exposes intralumenal glycans leading to galectin protein binding, subsequent autophagic protein recruitment, and, ultimately, their introduction into the autophagic-lysosomal pathway. Increasing evidence indicates that both pathological and non-pathological SNCA species undergo autophagy-dependent unconventional secretion. While other proteins have also been shown to be secreted from cells by autophagy, what triggers this release process and how these specific proteins are recruited to a secretory autophagic pathway is largely unknown. Here, we use a human midbrain dopamine (mDA) neuronal culture model to provide evidence in support of a cellular mechanism that explains the cell-to-cell transfer of pathological forms of SNCA that are observed in PD. We demonstrate that LGALS3 (galectin 3) mediates the release of SNCA following vesicular damage. SNCA release is also dependent on TRIM16 (tripartite motif containing 16) and ATG16L1 (autophagy related 16 like 1), providing evidence that secretion of SNCA is mediated by an autophagic secretory pathway.
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Affiliation(s)
- Kevin Burbidge
- Graduate Program in Neuroscience, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | - David J Rademacher
- Core Imaging Facility and Department of Microbiology and Immunology, Loyola University of Chicago, Maywood, Illinois, USA
| | - Jessica Mattick
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University, Chicago, Maywood, Illinois, USA
| | - Stephanie Zack
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University, Chicago, Maywood, Illinois, USA
| | - Andrea Grillini
- Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | - Luc Bousset
- Institut Francois Jacob (Mircen), Cea and Laboratory of Neurodegenerative Diseases, Cnrs, Fontenay-Aux-Roses Cedex, France
| | - Ochan Kwon
- Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | - Konrad Kubicki
- Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | - Alexander Simon
- Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | - Ronald Melki
- Institut Francois Jacob (Mircen), Cea and Laboratory of Neurodegenerative Diseases, Cnrs, Fontenay-Aux-Roses Cedex, France
| | - Edward M Campbell
- Graduate Program in Neuroscience, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA.,Core Imaging Facility and Department of Microbiology and Immunology, Loyola University of Chicago, Maywood, Illinois, USA
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36
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Lüth T, Wasner K, Klein C, Schaake S, Tse R, Pereira SL, Laß J, Sinkkonen L, Grünewald A, Trinh J. Nanopore Single-Molecule Sequencing for Mitochondrial DNA Methylation Analysis: Investigating Parkin-Associated Parkinsonism as a Proof of Concept. Front Aging Neurosci 2021; 13:713084. [PMID: 34650424 PMCID: PMC8506010 DOI: 10.3389/fnagi.2021.713084] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 09/01/2021] [Indexed: 01/08/2023] Open
Abstract
Objective: To establish a workflow for mitochondrial DNA (mtDNA) CpG methylation using Nanopore whole-genome sequencing and perform first pilot experiments on affected Parkin biallelic mutation carriers (Parkin-PD) and healthy controls. Background: Mitochondria, including mtDNA, are established key players in Parkinson's disease (PD) pathogenesis. Mutations in Parkin, essential for degradation of damaged mitochondria, cause early-onset PD. However, mtDNA methylation and its implication in PD is understudied. Herein, we establish a workflow using Nanopore sequencing to directly detect mtDNA CpG methylation and compare mtDNA methylation between Parkin-related PD and healthy individuals. Methods: To obtain mtDNA, whole-genome Nanopore sequencing was performed on blood-derived from five Parkin-PD and three control subjects. In addition, induced pluripotent stem cell (iPSC)-derived midbrain neurons from four of these patients with PD and the three control subjects were investigated. The workflow was validated, using methylated and unmethylated 897 bp synthetic DNA samples at different dilution ratios (0, 50, 100% methylation) and mtDNA without methylation. MtDNA CpG methylation frequency (MF) was detected using Nanopolish and Megalodon. Results: Across all blood-derived samples, we obtained a mean coverage of 250.3X (SD ± 80.5X) and across all neuron-derived samples 830X (SD ± 465X) of the mitochondrial genome. We detected overall low-level CpG methylation from the blood-derived DNA (mean MF ± SD = 0.029 ± 0.041) and neuron-derived DNA (mean MF ± SD = 0.019 ± 0.035). Validation of the workflow, using synthetic DNA samples showed that highly methylated DNA molecules were prone to lower Guppy Phred quality scores and thereby more likely to fail Guppy base-calling. CpG methylation in blood- and neuron-derived DNA was significantly lower in Parkin-PD compared to controls (Mann-Whitney U-test p < 0.05). Conclusion: Nanopore sequencing is a useful method to investigate mtDNA methylation architecture, including Guppy-failed reads is of importance when investigating highly methylated sites. We present a mtDNA methylation workflow and suggest methylation variability across different tissues and between Parkin-PD patients and controls as an initial model to investigate.
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Affiliation(s)
- Theresa Lüth
- Institute of Neurogenetics BMF, University of Lübeck and University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany
| | - Kobi Wasner
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
| | - Christine Klein
- Institute of Neurogenetics BMF, University of Lübeck and University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany
| | - Susen Schaake
- Institute of Neurogenetics BMF, University of Lübeck and University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany
| | - Ronnie Tse
- Institute of Neurogenetics BMF, University of Lübeck and University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany
| | - Sandro L. Pereira
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
| | - Joshua Laß
- Institute of Neurogenetics BMF, University of Lübeck and University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany
| | - Lasse Sinkkonen
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Anne Grünewald
- Institute of Neurogenetics BMF, University of Lübeck and University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
| | - Joanne Trinh
- Institute of Neurogenetics BMF, University of Lübeck and University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany
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37
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Behl T, Madaan P, Sehgal A, Singh S, Sharma N, Bhatia S, Al-Harrasi A, Chigurupati S, Alrashdi I, Bungau SG. Elucidating the Neuroprotective Role of PPARs in Parkinson's Disease: A Neoteric and Prospective Target. Int J Mol Sci 2021; 22:10161. [PMID: 34576325 PMCID: PMC8467926 DOI: 10.3390/ijms221810161] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 09/17/2021] [Accepted: 09/19/2021] [Indexed: 12/13/2022] Open
Abstract
One of the utmost frequently emerging neurodegenerative diseases, Parkinson's disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (P.M.); (A.S.); (S.S.); (N.S.)
| | - Piyush Madaan
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (P.M.); (A.S.); (S.S.); (N.S.)
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (P.M.); (A.S.); (S.S.); (N.S.)
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (P.M.); (A.S.); (S.S.); (N.S.)
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (P.M.); (A.S.); (S.S.); (N.S.)
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz 616, Nizwa P.O. Box 33, Oman; (S.B.); (A.A.-H.)
- School of Health Science, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Birkat Al Mauz 616, Nizwa P.O. Box 33, Oman; (S.B.); (A.A.-H.)
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah 52571, Saudi Arabia;
| | - Ibrahim Alrashdi
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK;
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410073 Oradea, Romania
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38
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Krajka V, Naujock M, Pauly MG, Stengel F, Meier B, Stanslowsky N, Klein C, Seibler P, Wegner F, Capetian P. Ventral Telencephalic Patterning Protocols for Induced Pluripotent Stem Cells. Front Cell Dev Biol 2021; 9:716249. [PMID: 34490265 PMCID: PMC8416478 DOI: 10.3389/fcell.2021.716249] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/30/2021] [Indexed: 11/25/2022] Open
Abstract
The differentiation of human induced pluripotent stem cells (hiPSCs) into specific cell types for disease modeling and restorative therapies is a key research agenda and offers the possibility to obtain patient-specific cells of interest for a wide range of diseases. Basal forebrain cholinergic neurons (BFCNs) play a particular role in the pathophysiology of Alzheimer’s dementia and isolated dystonias. In this work, various directed differentiation protocols based on monolayer neural induction were tested for their effectiveness in promoting a ventral telencephalic phenotype and generating BFCN. Ventralizing factors [i.e., purmorphamine and Sonic hedgehog (SHH)] were applied at different time points, time intervals, and concentrations. In addition, caudal identity was prevented by the use of a small molecule XAV-939 that inhibits the Wnt-pathway. After patterning, gene expression profiles were analyzed by quantitative PCR (qPCR). Rostro-ventral patterning is most effective when initiated simultaneously with neural induction. The most promising combination of patterning factors was 0.5 μM of purmorphamine and 1 μM of XAV-939, which induces the highest expression of transcription factors specific for the medial ganglionic eminence, the source of GABAergic inter- and cholinergic neurons in the telencephalon. Upon maturation of cells, the immune phenotype, as well as electrophysiological properties were investigated showing the presence of marker proteins specific for BFCN (choline acetyltransferase, ISL1, p75, and NKX2.1) and GABAergic neurons. Moreover, a considerable fraction of measured cells displayed mature electrophysiological properties. Synaptic boutons containing the vesicular acetylcholine transporter (VACHT) could be observed in the vicinity of the cells. This work will help to generate basal forebrain interneurons from hiPSCs, providing a promising platform for modeling neurological diseases, such as Alzheimer’s disease or Dystonia.
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Affiliation(s)
- Victor Krajka
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | | | - Martje G Pauly
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Felix Stengel
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Britta Meier
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | | | - Christine Klein
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Philip Seibler
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Florian Wegner
- Department of Neurology, Hannover Medical School, Hanover, Germany
| | - Philipp Capetian
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.,Department of Neurology, University Hospital Würzburg, Würzburg, Germany
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39
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Navarro E, Udine E, Lopes KDP, Parks M, Riboldi G, Schilder BM, Humphrey J, Snijders GJL, Vialle RA, Zhuang M, Sikder T, Argyrou C, Allan A, Chao MJ, Farrell K, Henderson B, Simon S, Raymond D, Elango S, Ortega RA, Shanker V, Swan M, Zhu CW, Ramdhani R, Walker RH, Tse W, Sano M, Pereira AC, Ahfeldt T, Goate AM, Bressman S, Crary JF, de Witte L, Frucht S, Saunders-Pullman R, Raj T. Dysregulation of mitochondrial and proteolysosomal genes in Parkinson's disease myeloid cells. NATURE AGING 2021; 1:850-863. [PMID: 35005630 PMCID: PMC8728893 DOI: 10.1038/s43587-021-00110-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 08/05/2021] [Indexed: 12/11/2022]
Abstract
An increasing number of identified Parkinson's disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, is altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.
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Affiliation(s)
- Elisa Navarro
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Evan Udine
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Katia de Paiva Lopes
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Madison Parks
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Giulietta Riboldi
- The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, NY, USA
- Universita degli Studi di Milano, Molecular and Translational Medicine, Milan, Italy
| | - Brian M Schilder
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jack Humphrey
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gijsje J L Snijders
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
- Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, NY, Bronx, USA
| | - Ricardo A Vialle
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maojuan Zhuang
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tamjeed Sikder
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Charalambos Argyrou
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amanda Allan
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael J Chao
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kurt Farrell
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brooklyn Henderson
- The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, NY, USA
| | - Sarah Simon
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Deborah Raymond
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sonya Elango
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Roberto A Ortega
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vicki Shanker
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matthew Swan
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Carolyn W Zhu
- Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Geriatric Research, Education and Clinical Centers, James J. Peters VA Medical Center, New York, NY, USA
- Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ritesh Ramdhani
- Department of Neurology, Zucker School of Medicine at Hofstra Northwell, New York, NY, USA
| | - Ruth H Walker
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, James J. Peters VA Medical Center, Bronx, NY, USA
| | - Winona Tse
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mary Sano
- Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Geriatric Research, Education and Clinical Centers, James J. Peters VA Medical Center, New York, NY, USA
- Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ana C Pereira
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tim Ahfeldt
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alison M Goate
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Susan Bressman
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John F Crary
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Lotje de Witte
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
- Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, NY, Bronx, USA
| | - Steven Frucht
- The Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, NY, USA
| | - Rachel Saunders-Pullman
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Towfique Raj
- Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Krzystek TJ, Banerjee R, Thurston L, Huang J, Swinter K, Rahman SN, Falzone TL, Gunawardena S. Differential mitochondrial roles for α-synuclein in DRP1-dependent fission and PINK1/Parkin-mediated oxidation. Cell Death Dis 2021; 12:796. [PMID: 34404758 PMCID: PMC8371151 DOI: 10.1038/s41419-021-04046-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 07/18/2021] [Accepted: 07/19/2021] [Indexed: 01/18/2023]
Abstract
Mitochondria are highly dynamic organelles with strict quality control processes that maintain cellular homeostasis. Within axons, coordinated cycles of fission-fusion mediated by dynamin related GTPase protein (DRP1) and mitofusins (MFN), together with regulated motility of healthy mitochondria anterogradely and damaged/oxidized mitochondria retrogradely, control mitochondrial shape, distribution and size. Disruption of this tight regulation has been linked to aberrant oxidative stress and mitochondrial dysfunction causing mitochondrial disease and neurodegeneration. Although pharmacological induction of Parkinson's disease (PD) in humans/animals with toxins or in mice overexpressing α-synuclein (α-syn) exhibited mitochondrial dysfunction and oxidative stress, mice lacking α-syn showed resistance to mitochondrial toxins; yet, how α-syn influences mitochondrial dynamics and turnover is unclear. Here, we isolate the mechanistic role of α-syn in mitochondrial homeostasis in vivo in a humanized Drosophila model of Parkinson's disease (PD). We show that excess α-syn causes fragmented mitochondria, which persists with either truncation of the C-terminus (α-syn1-120) or deletion of the NAC region (α-synΔNAC). Using in vivo oxidation reporters Mito-roGFP2-ORP1/GRX1 and MitoTimer, we found that α-syn-mediated fragments were oxidized/damaged, but α-syn1-120-induced fragments were healthy, suggesting that the C-terminus is required for oxidation. α-syn-mediated oxidized fragments showed biased retrograde motility, but α-syn1-120-mediated healthy fragments did not, demonstrating that the C-terminus likely mediates the retrograde motility of oxidized mitochondria. Depletion/inhibition or excess DRP1-rescued α-syn-mediated fragmentation, oxidation, and the biased retrograde motility, indicating that DRP1-mediated fragmentation is likely upstream of oxidation and motility changes. Further, excess PINK/Parkin, two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, rescued α-syn-mediated membrane depolarization, oxidation and cell death in a C-terminus-dependent manner, suggesting a functional interaction between α-syn and PINK/Parkin. Taken together, our findings identify distinct roles for α-syn in mitochondrial homeostasis, highlighting a previously unknown pathogenic pathway for the initiation of PD.
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Affiliation(s)
- Thomas J Krzystek
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, 14260, USA
| | - Rupkatha Banerjee
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, 14260, USA
| | - Layne Thurston
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, 14260, USA
| | - JianQiao Huang
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, 14260, USA
| | - Kelsey Swinter
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, 14260, USA
| | - Saad Navid Rahman
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, 14260, USA
| | - Tomas L Falzone
- Instituto de Biología Celular y Neurociencias IBCN (CONICET-UBA), Universidad De Buenos Aires, Buenos Aires, Argentina.,Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Shermali Gunawardena
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, 14260, USA.
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Luttrell SM, Smith AST, Mack DL. Creating stem cell-derived neuromuscular junctions in vitro. Muscle Nerve 2021; 64:388-403. [PMID: 34328673 PMCID: PMC9292444 DOI: 10.1002/mus.27360] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/28/2021] [Accepted: 06/21/2021] [Indexed: 12/14/2022]
Abstract
Recent development of novel therapies has improved mobility and quality of life for people suffering from inheritable neuromuscular disorders. Despite this progress, the majority of neuromuscular disorders are still incurable, in part due to a lack of predictive models of neuromuscular junction (NMJ) breakdown. Improvement of predictive models of a human NMJ would be transformative in terms of expanding our understanding of the mechanisms that underpin development, maintenance, and disease, and as a testbed with which to evaluate novel therapeutics. Induced pluripotent stem cells (iPSCs) are emerging as a clinically relevant and non‐invasive cell source to create human NMJs to study synaptic development and maturation, as well as disease modeling and drug discovery. This review will highlight the recent advances and remaining challenges to generating an NMJ capable of eliciting contraction of stem cell‐derived skeletal muscle in vitro. We explore the advantages and shortcomings of traditional NMJ culturing platforms, as well as the pioneering technologies and novel, biomimetic culturing systems currently in use to guide development and maturation of the neuromuscular synapse and extracellular microenvironment. Then, we will explore how this NMJ‐in‐a‐dish can be used to study normal assembly and function of the efferent portion of the neuromuscular arc, and how neuromuscular disease‐causing mutations disrupt structure, signaling, and function.
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Affiliation(s)
- Shawn M Luttrell
- Department of Rehabilitation Medicine, University of Washington, Seattle, Washington, USA.,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA
| | - Alec S T Smith
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.,Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA
| | - David L Mack
- Department of Rehabilitation Medicine, University of Washington, Seattle, Washington, USA.,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.,Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA
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Valiulahi P, Vidyawan V, Puspita L, Oh Y, Juwono VB, Sittipo P, Friedlander G, Yahalomi D, Sohn JW, Lee YK, Yoon JK, Shim JW. Generation of caudal-type serotonin neurons and hindbrain-fate organoids from hPSCs. Stem Cell Reports 2021; 16:1938-1952. [PMID: 34242615 PMCID: PMC8365029 DOI: 10.1016/j.stemcr.2021.06.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 06/08/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Serotonin (5-HT) neurons, the major components of the raphe nuclei, arise from ventral hindbrain progenitors. Based on anatomical location and axonal projection, 5-HT neurons are coarsely divided into rostral and caudal groups. Here, we propose a novel strategy to generate hindbrain 5-HT neurons from human pluripotent stem cells (hPSCs), which involves the formation of ventral-type neural progenitor cells and stimulation of the hindbrain 5-HT neural development. A caudalizing agent, retinoid acid, was used to direct the cells into the hindbrain cell fate. Approximately 30%–40% of hPSCs successfully developed into 5-HT-expressing neurons using our protocol, with the majority acquiring a caudal rhombomere identity (r5–8). We further modified our monolayer differentiation system to generate 5-HT neuron-enriched hindbrain-like organoids. We also suggest downstream applications of our 5-HT monolayer and organoid cultures to study neuronal response to gut microbiota. Our methodology could become a powerful tool for future studies related to 5-HT neurotransmission.
Activation of SHH and RA signaling induces 5-HT neuronal fate from hPSCs The generated 5-HT neurons have caudal hindbrain characteristics Hindbrain-like organoids may form from hPSCs by activation of SHH and RA signaling 5-HT neurons in monolayer and organoid culture can be used as a screening platform
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Affiliation(s)
- Parvin Valiulahi
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea; Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Korea
| | - Vincencius Vidyawan
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea; Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Korea
| | - Lesly Puspita
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea; Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Korea
| | - Youjin Oh
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
| | - Virginia Blessy Juwono
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea; Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Korea
| | - Panida Sittipo
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea; Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Korea
| | - Gilgi Friedlander
- The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Dayana Yahalomi
- The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Jong-Woo Sohn
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
| | - Yun Kyung Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea; Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Korea.
| | - Jeong Kyo Yoon
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea; Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Korea.
| | - Jae-Won Shim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25, Bongjeong-ro, Dongnam-gu, Cheonan-si 31151, Korea; Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Korea.
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Mitophagy and Oxidative Stress: The Role of Aging. Antioxidants (Basel) 2021; 10:antiox10050794. [PMID: 34067882 PMCID: PMC8156559 DOI: 10.3390/antiox10050794] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/12/2021] [Accepted: 05/15/2021] [Indexed: 02/07/2023] Open
Abstract
Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer’s and Parkinson’s diseases. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, or an alteration in the regulation of mitophagy leading to the excessive production of ROS by damaged mitochondria.
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Pérez MJ, Baden P, Deleidi M. Progresses in both basic research and clinical trials of NAD+ in Parkinson's disease. Mech Ageing Dev 2021; 197:111499. [PMID: 33989633 DOI: 10.1016/j.mad.2021.111499] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/07/2021] [Accepted: 05/07/2021] [Indexed: 10/21/2022]
Abstract
The decline of nicotinamide adenine dinucleotide (NAD+) levels is a hallmark of aging in multiple organisms and tissues, including the human brain. Hence, agents that increase intracellular NAD+ could have beneficial effects in aging and age-related neurodegenerative diseases. Disturbances in NAD+ metabolism have also been observed in Parkinson's disease (PD), supporting a link between neuronal bioenergetics failure and disease pathogenesis. Here, we review emerging findings revealing key roles for NAD+ and related metabolites in experimental models of dopaminergic neurodegeneration and in PD patients. We discuss how increased NAD+ levels might ameliorate disease phenotypes by restoring neuronal mitochondrial energy metabolism, promoting cellular proteostasis, and modulating the immune system. Finally, we describe ongoing clinical trials targeting NAD+ in PD and highlight the need for further investigations to better delineate the association between NAD+, brain aging and disease, and optimal strategies for efficiently and safely raising NAD+ levels. A more comprehensive understanding of the basic mechanisms linking NAD+, energy metabolism, and PD, and of the impact of life-long NAD+ targeting strategies, are critical to inform future clinical applications.
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Affiliation(s)
- María José Pérez
- German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany; Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany
| | - Pascale Baden
- German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany; Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany
| | - Michela Deleidi
- German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany; Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.
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Zhou Q, Xie M, Zhu J, Yi Q, Tan B, Li Y, Ye L, Zhang X, Zhang Y, Tian J, Xu H. PINK1 contained in huMSC-derived exosomes prevents cardiomyocyte mitochondrial calcium overload in sepsis via recovery of mitochondrial Ca 2+ efflux. Stem Cell Res Ther 2021; 12:269. [PMID: 33957982 PMCID: PMC8101124 DOI: 10.1186/s13287-021-02325-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 04/03/2021] [Indexed: 01/13/2023] Open
Abstract
Background Sepsis is a systemic inflammatory response to a local severe infection that may lead to multiple organ failure and death. Previous studies have shown that 40–50% of patients with sepsis have diverse myocardial injuries and 70 to 90% mortality rates compared to 20% mortality in patients with sepsis without myocardial injury. Therefore, uncovering the mechanism of sepsis-induced myocardial injury and finding a target-based treatment are immensely important. Objective The present study elucidated the mechanism of sepsis-induced myocardial injury and examined the value of human umbilical cord mesenchymal stem cells (huMSCs) for protecting cardiac function in sepsis. Methods We used cecal ligation and puncture (CLP) to induce sepsis in mice and detect myocardial injury and cardiac function using serological markers and echocardiography. Cardiomyocyte apoptosis and heart tissue ultrastructure were detected using TdT-mediated dUTP Nick-End Labeling (TUNEL) and transmission electron microscopy (TEM), respectively. Fura-2 AM was used to monitor Ca2+ uptake and efflux in mitochondria. FQ-PCR and Western blotting detected expression of mitochondrial Ca2+ distribution regulators and PTEN-induced putative kinase 1 (PINK1). JC-1 was used to detect the mitochondrial membrane potential (Δψm) of cardiomyocytes. Results We found that expression of PINK1 decreased in mouse hearts during sepsis, which caused cardiomyocyte mitochondrial Ca2+ efflux disorder, mitochondrial calcium overload, and cardiomyocyte injury. In contrast, we found that exosomes isolated from huMSCs (huMSC-exo) carried Pink1 mRNA, which could be transferred to recipient cardiomyocytes to increase PINK1 expression. The reduction in cardiomyocyte mitochondrial calcium efflux was reversed, and cardiomyocytes recovered from injury. We confirmed the effect of the PINK1-PKA-NCLX axis on mitochondrial calcium homeostasis in cardiomyocytes during sepsis. Conclusion The PINK1-PKA-NCLX axis plays an important role in mitochondrial calcium efflux in cardiomyocytes. Therefore, PINK1 may be a therapeutic target to protect cardiomyocyte mitochondria, and the application of huMSC-exo is a promising strategy against sepsis-induced heart dysfunction. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02325-6.
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Affiliation(s)
- Qin Zhou
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Min Xie
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Jing Zhu
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Qin Yi
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Bin Tan
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Yasha Li
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Liang Ye
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Xinyuan Zhang
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Ying Zhang
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Jie Tian
- Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.,Department of Cardiovascular (Internal Medicine), Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Hao Xu
- Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China. .,Department of Clinical Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Box 136, No. 3 Zhongshan RD, Yuzhong district, Chongqing, 400014, People's Republic of China.
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Gonçalves FB, Morais VA. PINK1: A Bridge between Mitochondria and Parkinson's Disease. Life (Basel) 2021; 11:life11050371. [PMID: 33919398 PMCID: PMC8143285 DOI: 10.3390/life11050371] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 12/31/2022] Open
Abstract
Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson’s disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.
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Current State-of-the-Art and Unresolved Problems in Using Human Induced Pluripotent Stem Cell-Derived Dopamine Neurons for Parkinson's Disease Drug Development. Int J Mol Sci 2021; 22:ijms22073381. [PMID: 33806103 PMCID: PMC8037675 DOI: 10.3390/ijms22073381] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/15/2021] [Accepted: 03/22/2021] [Indexed: 12/11/2022] Open
Abstract
Human induced pluripotent stem (iPS) cells have the potential to give rise to a new era in Parkinson's disease (PD) research. As a unique source of midbrain dopaminergic (DA) neurons, iPS cells provide unparalleled capabilities for investigating the pathogenesis of PD, the development of novel anti-parkinsonian drugs, and personalized therapy design. Significant progress in developmental biology of midbrain DA neurons laid the foundation for their efficient derivation from iPS cells. The introduction of 3D culture methods to mimic the brain microenvironment further expanded the vast opportunities of iPS cell-based research of the neurodegenerative diseases. However, while the benefits for basic and applied studies provided by iPS cells receive widespread coverage in the current literature, the drawbacks of this model in its current state, and in particular, the aspects of differentiation protocols requiring further refinement are commonly overlooked. This review summarizes the recent data on general and subtype-specific features of midbrain DA neurons and their development. Here, we review the current protocols for derivation of DA neurons from human iPS cells and outline their general weak spots. The associated gaps in the contemporary knowledge are considered and the possible directions for future research that may assist in improving the differentiation conditions and increase the efficiency of using iPS cell-derived neurons for PD drug development are discussed.
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Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder resulting from the death of dopamine neurons in the substantia nigra pars compacta. Our understanding of PD biology has been enriched by the identification of genes involved in its rare, inheritable forms, termed PARK genes. These genes encode proteins including α-syn, LRRK2, VPS35, parkin, PINK1, and DJ1, which can cause monogenetic PD when mutated. Investigating the cellular functions of these proteins has been instrumental in identifying signaling pathways that mediate pathology in PD and neuroprotective mechanisms active during homeostatic and pathological conditions. It is now evident that many PD-associated proteins perform multiple functions in PD-associated signaling pathways in neurons. Furthermore, several PARK proteins contribute to non-cell-autonomous mechanisms of neuron death, such as neuroinflammation. A comprehensive understanding of cell-autonomous and non-cell-autonomous pathways involved in PD is essential for developing therapeutics that may slow or halt its progression.
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Affiliation(s)
- Nikhil Panicker
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Preston Ge
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA
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49
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Modelling Parkinson's Disease: iPSCs towards Better Understanding of Human Pathology. Brain Sci 2021; 11:brainsci11030373. [PMID: 33799491 PMCID: PMC8000082 DOI: 10.3390/brainsci11030373] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/10/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023] Open
Abstract
Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.
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50
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MacDougall G, Brown LY, Kantor B, Chiba-Falek O. The Path to Progress Preclinical Studies of Age-Related Neurodegenerative Diseases: A Perspective on Rodent and hiPSC-Derived Models. Mol Ther 2021; 29:949-972. [PMID: 33429080 PMCID: PMC7934639 DOI: 10.1016/j.ymthe.2021.01.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/03/2020] [Accepted: 01/01/2021] [Indexed: 12/21/2022] Open
Abstract
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent age-related neurodegenerative diseases, and currently no effective clinical treatments exist for either, despite decades of clinical trials. The failure to translate preclinical findings into effective treatments is indicative of a problem in the current evaluation pipeline for potential therapeutics. At present, there are no useful animal models for AD and PD research that reflect the entire biology of the diseases, specifically, the more common non-Mendelian forms. Whereas the field continues to seek suitable rodent models for investigating potential therapeutics for these diseases, rodent models have still been used primarily for preclinical studies. Here, we advocate for a paradigm shift toward the application of human-induced pluripotent stem cell (hiPSC)-derived systems for PD and AD modeling and the development of improved human-based models in a dish for drug discovery and preclinical assessment of therapeutic targets.
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Affiliation(s)
- Gabriella MacDougall
- Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Logan Y Brown
- Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Center for Advanced Genomic Technologies, Duke University Medical Center, Durham, NC 27710, USA; Viral Vector Core, Duke University Medical Center, Durham, NC 27710, USA
| | - Boris Kantor
- Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Center for Advanced Genomic Technologies, Duke University Medical Center, Durham, NC 27710, USA; Viral Vector Core, Duke University Medical Center, Durham, NC 27710, USA.
| | - Ornit Chiba-Falek
- Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27710, USA.
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