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1
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Manav N, Sharma P, Mochan S, Malhotra L. Unraveling the unique amyloid-like aggregation behavior of the tumor suppressor p53 mutants in human cancers. Int J Biol Macromol 2025; 311:143883. [PMID: 40319958 DOI: 10.1016/j.ijbiomac.2025.143883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/19/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Missense mutations in the tumor suppressor p53 significantly disrupt its native structure and functions, playing a pivotal role in human cancer pathogenesis. Oncogenic mutant p53 (mutp53) not only loses its tumor-suppressive capabilities but also acquires oncogenic functions, driving cancer progression, metastasis, and chemoresistance. Despite extensive research on mutp53, the role of missense mutations in triggering amyloid-like aggregation of p53 remains an underexplored and fascinating area of study. To date, over 50 proteins are known to form amyloid-like aggregates due to abnormal folding, resulting in insoluble protein fibrils that contribute to various protein misfolding diseases, including cancer. However, the precise mechanisms by which aggregated proteins induce cancer remain inadequately understood. Notably, certain p53 mutations promote its aggregation, which has emerged as a critical factor in protein aggregation-induced oncogenesis. This review delves into the mechanisms underpinning mutp53 aggregation, emphasizing unique properties such as coaggregation, bio-isolation, prion-like cell-to-cell transmission, and chemoresistance promotion. Leveraging diverse in-silico, biophysical, and biochemical approaches, we comprehensively analyzed the aggregating potential of 26 mutp53 variants among 1297 missense mutations identified in human cancers. These findings shed light on the multifaceted roles of mutp53 aggregates in oncogenesis and tumor progression. Lastly, we present an integrative exploration of emerging therapeutic strategies designed to disaggregate mutp53 aggregates, offering promising directions for targeted cancer therapy. By addressing this enigmatic aspect of mutp53 biology, our review advances the understanding of protein aggregation in cancer and identifies avenues for innovative therapeutic interventions.
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Affiliation(s)
- Nisha Manav
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Pratibha Sharma
- Department of Neurology, Institute of Human Behaviour and Allied Sciences, Delhi 110095, India
| | - Sankat Mochan
- Department of Anatomy, University College of Medical Sciences, University of Delhi, Delhi 110095, India
| | - Lakshay Malhotra
- Department of Biochemistry, Sri Venkateswara College, University of Delhi, New Delhi 110021, India.
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Eltayeb A, Rubio-Casillas A, Uversky VN, Redwan EM. Intrinsic Factors Behind Long COVID: VI. Combined Impact of G3BPs and SARS-CoV-2 Nucleocapsid Protein on the Viral Persistence and Long COVID. J Cell Biochem 2025; 126:e70038. [PMID: 40415285 DOI: 10.1002/jcb.70038] [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: 04/27/2025] [Revised: 04/27/2025] [Accepted: 05/11/2025] [Indexed: 05/27/2025]
Abstract
The efficient transmission of SARS-CoV-2 caused the COVID-19 pandemic, which affected millions of people around the globe. Despite extensive efforts, specific therapeutic interventions and preventive measures against COVID-19 and its consequences, such as long COVID, have not yet been identified due to the lack of a comprehensive knowledge of the SARS-CoV-2 biology. Therefore, a deeper understanding of the sophisticated strategies employed by SARS-CoV-2 to bypass the host antiviral defense systems is needed. One of these strategies is the inhibition of the Ras GTPase-activating protein-binding protein (GAP SH3-binding protein or G3BP)-dependent host immune response by the SARS-CoV-2 nucleocapsid (N) protein. This inhibition disrupts the formation of stress granules (SGs), which are crucial for antiviral defense. By preventing SG formation, the virus enhances its replication and evades the host's immune response, leading to increased disease severity. Given the involvement of G3BP1 in SG formation and its ability to interact with viral proteins, along with the crucial role of the N protein in the replication of the virus, we hypothesize that these proteins may have a potential role in the pathogenesis of long COVID. Despite the current lack of direct evidence linking these proteins to long COVID, their interactions and functions suggest a possible connection that warrants further investigation.
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Affiliation(s)
- Ahmed Eltayeb
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Alberto Rubio-Casillas
- Autlan Regional Hospital, Jalisco Health Services, Autlan, Jalisco, Mexico
- Biology Laboratory, Autlan Regional Preparatory School, University of Guadalajara, Autlan, Jalisco, Mexico
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Elrashdy M Redwan
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Excellence in Bionanoscience Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Protein Research Department, Therapeutic and Protective Proteins Laboratory, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria, Egypt
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Rinaldi A, Balietti M, Principi E, De Luca M, De Felice E, Narcisi FM, Vilardo L, Rosito M, Piacentini R, D'Alessandro G, D'Agnano I, Maggi L, Conti F, Limatola C, Catalano M. BV2-derived extracellular vesicles modulate microglia inflammatory profile, neuronal plasticity, and behavioural performances in late adult mice. Brain Behav Immun 2024; 122:58-74. [PMID: 39128568 DOI: 10.1016/j.bbi.2024.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/24/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND During aging, both the brain and the immune system undergo a progressive impairment of physiological functions. Microglia, the immunocompetent cells of the central nervous system, shift towards a chronic mild inflammatory state that impacts brain homeostasis. Extracellular vesicles (EVs) released by microglia transport packages of molecular information that mirror the inflammatory status of donor cells and modulate the inflammatory phenotype of recipient microglia and other cell types. RESULTS We demonstrated that intranasal administration of EVs derived from microglial-like BV2 cells to late adult mice (16-20 months of age) shifts microglia toward a "juvenile" morphology affecting their inflammatory profile. Mice treated with BV2-derived EVs have a reduction of anxiety-like behavior and an increased spatial learning, with sex-dependent differences. Further, BV2-derived EVs increased neuronal plasticity both in male and female mice. These findings suggest the involvement of microglial cells in vesicles-mediated anti-aging effect. CONCLUSIONS Our data indicate that BV2-derived EVs could represent a resource to slow down age-dependent inflammation in the mouse brain.
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Affiliation(s)
- Arianna Rinaldi
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Marta Balietti
- IRCCS INRCA, Center for Neurobiology of Aging, Via Birarelli 8, Ancona 60121, Italy
| | - Elisa Principi
- Università Politecnica delle Marche, Department of Experimental and Clinical Medicine, Via Tronto 10/a, Ancona 60126, Italy
| | | | - Eleonora De Felice
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | | | - Laura Vilardo
- Institute of Biomedical Technologies, CNR, 20054 Segrate, Italy
| | - Maria Rosito
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; Center for Life Nanoscience & Neuroscience Istituto Italiano di Tecnologia@Sapienza, Rome, Italy
| | - Roberto Piacentini
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy; IRCCS Fondazione Policlinico Universitario A. Gemelli, Largo A. Gemelli 1, Roma, Italy
| | - Giuseppina D'Alessandro
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; IRCCS Neuromed, Pozzilli, IS, Italy
| | - Igea D'Agnano
- Institute of Biomedical Technologies, CNR, 20054 Segrate, Italy
| | - Laura Maggi
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Fiorenzo Conti
- Università Politecnica delle Marche, Department of Experimental and Clinical Medicine, Via Tronto 10/a, Ancona 60126, Italy; IRCCS INRCA, Center for Neurobiology of Aging, Via Birarelli 8, Ancona 60121, Italy
| | - Cristina Limatola
- IRCCS Neuromed, Pozzilli, IS, Italy; Department of Physiology and Pharmacology, Sapienza University, Laboratory affiliated to Institute Pasteur Italia, Rome, Italy
| | - Myriam Catalano
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
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Kell DB, Pretorius E. Proteomic Evidence for Amyloidogenic Cross-Seeding in Fibrinaloid Microclots. Int J Mol Sci 2024; 25:10809. [PMID: 39409138 PMCID: PMC11476703 DOI: 10.3390/ijms251910809] [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: 09/17/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 10/20/2024] Open
Abstract
In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils and fibrils exhibiting a cross-β motif of parallel or antiparallel β-sheets oriented perpendicular to the fibre direction. These protofibrils and fibrils can intertwine to form mature amyloid fibres. Similar phenomena can occur in blood from individuals with circulating inflammatory molecules (and also some originating from viruses and bacteria). Such pathological clotting can result in an anomalous amyloid form termed fibrinaloid microclots. Previous proteomic analyses of these microclots have shown the presence of non-fibrin(ogen) proteins, suggesting a more complex mechanism than simple entrapment. We thus provide evidence against such a simple entrapment model, noting that clot pores are too large and centrifugation would have removed weakly bound proteins. Instead, we explore whether co-aggregation into amyloid fibres may involve axial (multiple proteins within the same fibril), lateral (single-protein fibrils contributing to a fibre), or both types of integration. Our analysis of proteomic data from fibrinaloid microclots in different diseases shows no significant quantitative overlap with the normal plasma proteome and no correlation between plasma protein abundance and their presence in fibrinaloid microclots. Notably, abundant plasma proteins like α-2-macroglobulin, fibronectin, and transthyretin are absent from microclots, while less abundant proteins such as adiponectin, periostin, and von Willebrand factor are well represented. Using bioinformatic tools, including AmyloGram and AnuPP, we found that proteins entrapped in fibrinaloid microclots exhibit high amyloidogenic tendencies, suggesting their integration as cross-β elements into amyloid structures. This integration likely contributes to the microclots' resistance to proteolysis. Our findings underscore the role of cross-seeding in fibrinaloid microclot formation and highlight the need for further investigation into their structural properties and implications in thrombotic and amyloid diseases. These insights provide a foundation for developing novel diagnostic and therapeutic strategies targeting amyloidogenic cross-seeding in blood clotting disorders.
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Affiliation(s)
- Douglas B. Kell
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Crown St., Liverpool L69 7ZB, UK
- The Novo Nordisk Foundation Centre for Biosustainability, Building 220, Søltofts Plads 200, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch 7602, South Africa
| | - Etheresia Pretorius
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Crown St., Liverpool L69 7ZB, UK
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch 7602, South Africa
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5
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Frey L, Ghosh D, Qureshi BM, Rhyner D, Guerrero-Ferreira R, Pokharna A, Kwiatkowski W, Serdiuk T, Picotti P, Riek R, Greenwald J. On the pH-dependence of α-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation. eLife 2024; 12:RP93562. [PMID: 39196271 PMCID: PMC11357353 DOI: 10.7554/elife.93562] [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: 08/29/2024] Open
Abstract
The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical significance. However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the α-synuclein fibrils hampers efforts in disease-relevant in vitro studies on α-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of α-synuclein fibrils in vitro as a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8-7.4, a pH-dependent selection between Type 1, 2, and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structure in vitro.
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Affiliation(s)
- Lukas Frey
- Institute of Molecular Physical ScienceZürichSwitzerland
| | - Dhiman Ghosh
- Institute of Molecular Physical ScienceZürichSwitzerland
| | - Bilal M Qureshi
- Scientific Center for Optical and Electron MicroscopyZürichSwitzerland
| | - David Rhyner
- Institute of Molecular Physical ScienceZürichSwitzerland
| | | | | | | | - Tetiana Serdiuk
- Institute of Molecular Systems Biology, ETH ZürichZurichSwitzerland
| | - Paola Picotti
- Institute of Molecular Systems Biology, ETH ZürichZurichSwitzerland
| | - Roland Riek
- Institute of Molecular Physical ScienceZürichSwitzerland
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Tullo S, Miranda AS, Del Cid-Pellitero E, Lim MP, Gallino D, Attaran A, Patel R, Novikov V, Park M, Beraldo FH, Luo W, Shlaifer I, Durcan TM, Bussey TJ, Saksida LM, Fon EA, Prado VF, Prado MAM, Chakravarty MM. Neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy prior to onset of motor symptoms. J Neurochem 2024; 168:1546-1564. [PMID: 37804203 DOI: 10.1111/jnc.15967] [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: 01/23/2023] [Revised: 08/31/2023] [Accepted: 09/11/2023] [Indexed: 10/09/2023]
Abstract
Significant evidence suggests that misfolded alpha-synuclein (aSyn), a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha-synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human-relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF-injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human-relevant pre-clinical measures and suggest that these pre-clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease.
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Affiliation(s)
- Stephanie Tullo
- Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
| | - Aline S Miranda
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Departamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Esther Del Cid-Pellitero
- McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
| | - Mei Peng Lim
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Daniel Gallino
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
| | - Anoosha Attaran
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Raihaan Patel
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
- Department of Biological & Biomedical Engineering, McGill University, Montreal, Quebec, Canada
| | - Vladislav Novikov
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Megan Park
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
| | - Flavio H Beraldo
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Wen Luo
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Irina Shlaifer
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Thomas M Durcan
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Timothy J Bussey
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Lisa M Saksida
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Edward A Fon
- McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
| | - Vania F Prado
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Marco A M Prado
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - M Mallar Chakravarty
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
- Department of Biological & Biomedical Engineering, McGill University, Montreal, Quebec, Canada
- Department of Psychiatry, McGill University, Montreal, Quebec, Canada
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7
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Buchholz S, Zempel H. The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes. Alzheimers Dement 2024; 20:3606-3628. [PMID: 38556838 PMCID: PMC11095451 DOI: 10.1002/alz.13784] [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: 12/08/2023] [Revised: 02/08/2024] [Accepted: 02/12/2024] [Indexed: 04/02/2024]
Abstract
INTRODUCTION Alternative splicing of the human MAPT gene generates six brain-specific TAU isoforms. Imbalances in the TAU isoform ratio can lead to neurodegenerative diseases, underscoring the need for precise control over TAU isoform balance. Tauopathies, characterized by intracellular aggregates of hyperphosphorylated TAU, exhibit extensive neurodegeneration and can be classified by the TAU isoforms present in pathological accumulations. METHODS A comprehensive review of TAU and related dementia syndromes literature was conducted using PubMed, Google Scholar, and preprint server. RESULTS While TAU is recognized as key driver of neurodegeneration in specific tauopathies, the contribution of the isoforms to neuronal function and disease development remains largely elusive. DISCUSSION In this review we describe the role of TAU isoforms in health and disease, and stress the importance of comprehending and studying TAU isoforms in both, physiological and pathological context, in order to develop targeted therapeutic interventions for TAU-associated diseases. HIGHLIGHTS MAPT splicing is tightly regulated during neuronal maturation and throughout life. TAU isoform expression is development-, cell-type and brain region specific. The contribution of TAU to neurodegeneration might be isoform-specific. Ineffective TAU-based therapies highlight the need for specific targeting strategies.
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Affiliation(s)
- Sarah Buchholz
- Institute of Human GeneticsFaculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany
- Center for Molecular Medicine Cologne (CMMC)University of CologneCologneGermany
- Present address:
Department Schaefer, Neurobiology of AgeingMax Planck Institute for Biology of AgeingCologneGermany
| | - Hans Zempel
- Institute of Human GeneticsFaculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany
- Center for Molecular Medicine Cologne (CMMC)University of CologneCologneGermany
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8
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Yan J, Liu D, Wang J, You W, Yang W, Yan S, He W. Rewiring chaperone-mediated autophagy in cancer by a prion-like chemical inducer of proximity to counteract adaptive immune resistance. Drug Resist Updat 2024; 73:101037. [PMID: 38171078 DOI: 10.1016/j.drup.2023.101037] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/05/2024]
Abstract
Chaperone-mediated autophagy (CMA), a proteolytic system contributing to the degradation of intracellular proteins in lysosomes, is upregulated in tumors for pro-tumorigenic and pro-survival purposes. In this study, bioinformatics analysis revealed the co-occurrence of upregulated CMA and PD-L1 accumulation in metastatic melanoma with adaptive immune resistance (AIR) to anti-PD1 treatment, suggesting the potential therapeutic effects of rewiring CMA for PD-L1 degradation. Furthermore, this co-occurrence is attributed to IFN-γ-mediated compensatory up-regulation of PD-L1 and CMA, accompanied by enhanced macropinocytosis. Drawing inspiration from the cellular uptake of prions via macropinocytosis, a prion-like chemical inducer of proximity called SAP was engineered using self-assembly of the designed chiral peptide PHA. By exploiting sensitized macropinocytosis, SAP clandestinely infiltrates tumor cells and subsequently disintegrates into PHA, which reprograms CMA by inducing PD-L1 close to HSPA8. SAP degrades PD-L1 in a CMA-dependent manner and effectively restores the anti-tumor immune response in both allografting and Hu-PDX melanoma mouse models with AIR while upholding a high safety profile. Collectively, the reported SAP not only presents an immune reactivation strategy with clinical translational potential for overcoming AIR in cutaneous melanomas but serves as a reproducible example of precision-medicine-guided drug development that fully leverages specific cellular indications in pathological states.
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Affiliation(s)
- Jin Yan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China; National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China.
| | - Dan Liu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China
| | - Jingmei Wang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China; Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Weiming You
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
| | - Wenguang Yang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China
| | - Siqi Yan
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Wangxiao He
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China; Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China.
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9
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Hu C, Yan Y, Jin Y, Yang J, Xi Y, Zhong Z. Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases. Neurosci Bull 2024; 40:241-254. [PMID: 37755677 PMCID: PMC10838874 DOI: 10.1007/s12264-023-01115-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 07/02/2023] [Indexed: 09/28/2023] Open
Abstract
The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
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Affiliation(s)
- Chenjun Hu
- Department of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yiqun Yan
- Department of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yanhong Jin
- Department of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jun Yang
- Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yongmei Xi
- Division of Human Reproduction and Developmental Genetics, Women's Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Zhen Zhong
- Department of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
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10
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Filannino FM, Panaro MA, Benameur T, Pizzolorusso I, Porro C. Extracellular Vesicles in the Central Nervous System: A Novel Mechanism of Neuronal Cell Communication. Int J Mol Sci 2024; 25:1629. [PMID: 38338906 PMCID: PMC10855168 DOI: 10.3390/ijms25031629] [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: 12/21/2023] [Revised: 01/21/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Cell-to-cell communication is essential for the appropriate development and maintenance of homeostatic conditions in the central nervous system. Extracellular vesicles have recently come to the forefront of neuroscience as novel vehicles for the transfer of complex signals between neuronal cells. Extracellular vesicles are membrane-bound carriers packed with proteins, metabolites, and nucleic acids (including DNA, mRNA, and microRNAs) that contain the elements present in the cell they originate from. Since their discovery, extracellular vesicles have been studied extensively and have opened up new understanding of cell-cell communication; they may cross the blood-brain barrier in a bidirectional way from the bloodstream to the brain parenchyma and vice versa, and play a key role in brain-periphery communication in physiology as well as pathology. Neurons and glial cells in the central nervous system release extracellular vesicles to the interstitial fluid of the brain and spinal cord parenchyma. Extracellular vesicles contain proteins, nucleic acids, lipids, carbohydrates, and primary and secondary metabolites. that can be taken up by and modulate the behaviour of neighbouring recipient cells. The functions of extracellular vesicles have been extensively studied in the context of neurodegenerative diseases. The purpose of this review is to analyse the role extracellular vesicles extracellular vesicles in central nervous system cell communication, with particular emphasis on the contribution of extracellular vesicles from different central nervous system cell types in maintaining or altering central nervous system homeostasis.
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Affiliation(s)
| | - Maria Antonietta Panaro
- Department of Biosciences, Biotechnologies and Environment, University of Bari, 70125 Bari, Italy;
| | - Tarek Benameur
- Department of Biomedical Sciences, College of Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Ilaria Pizzolorusso
- Child and Adolescent Neuropsychiatry Unit, Department of Mental Health, ASL Foggia, 71121 Foggia, Italy;
| | - Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy;
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11
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Izquierdo-Altarejos P, Moreno-Manzano V, Felipo V. Pathological and therapeutic effects of extracellular vesicles in neurological and neurodegenerative diseases. Neural Regen Res 2024; 19:55-61. [PMID: 37488844 PMCID: PMC10479838 DOI: 10.4103/1673-5374.375301] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/08/2023] [Accepted: 04/20/2023] [Indexed: 07/26/2023] Open
Abstract
Extracellular vesicles are released by all cell types and contain proteins, microRNAs, mRNAs, and other bioactive molecules. Extracellular vesicles play an important role in intercellular communication and in the modulation of the immune system and neuroinflammation. The cargo of extracellular vesicles (e.g., proteins and microRNAs) is altered in pathological situations. Extracellular vesicles contribute to the pathogenesis of many pathologies associated with sustained inflammation and neuroinflammation, including cancer, diabetes, hyperammonemia and hepatic encephalopathy, and other neurological and neurodegenerative diseases. Extracellular vesicles may cross the blood-brain barrier and transfer pathological signals from the periphery to the brain. This contributes to inducing neuroinflammation and cognitive and motor impairment in hyperammonemia and hepatic encephalopathy and in neurodegenerative diseases. The mechanisms involved are beginning to be understood. For example, increased tumor necrosis factor α in extracellular vesicles from plasma of hyperammonemic rats induces neuroinflammation and motor impairment when injected into normal rats. Identifying the mechanisms by which extracellular vesicles contribute to the pathogenesis of these diseases will help to develop new treatments and diagnostic tools for their easy and early detection. In contrast, extracellular vesicles from mesenchymal stem cells have therapeutic utility in many of the above pathologies, by reducing inflammation and neuroinflammation and improving cognitive and motor function. These extracellular vesicles recapitulate the beneficial effects of mesenchymal stem cells and have advantages as therapeutic tools: they are less immunogenic, may not differentiate to malignant cells, cross the blood-brain barrier, and may reach more easily target organs. Extracellular vesicles from mesenchymal stem cells have beneficial effects in models of ischemic brain injury, Alzheimer's and Parkinson's diseases, hyperammonemia, and hepatic encephalopathy. Extracellular vesicles from mesenchymal stem cells modulate the immune system, promoting the shift from a pro-inflammatory to an anti-inflammatory state. For example, extracellular vesicles from mesenchymal stem cells modulate the Th17/Treg balance, promoting the anti-inflammatory Treg. Extracellular vesicles from mesenchymal stem cells may also act directly in the brain to modulate microglia activation, promoting a shift from a pro-inflammatory to an anti-inflammatory state. This reduces neuroinflammation and improves cognitive and motor function. Two main components of extracellular vesicles from mesenchymal stem cells which contribute to these beneficial effects are transforming growth factor-β and miR-124. Identifying the mechanisms by which extracellular vesicles from mesenchymal stem cells induce the beneficial effects and the main molecules (e.g., proteins and mRNAs) involved may help to improve their therapeutic utility. The aims of this review are to summarize the knowledge of the pathological effects of extracellular vesicles in different pathologies, the therapeutic potential of extracellular vesicles from mesenchymal stem cells to recover cognitive and motor function and the molecular mechanisms for these beneficial effects on neurological function.
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Affiliation(s)
| | - Victoria Moreno-Manzano
- Neuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain
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12
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Aguilar-Calvo P, Malik A, Sandoval DR, Barback C, Orrù CD, Standke HG, Thomas OR, Dwyer CA, Pizzo DP, Bapat J, Soldau K, Ogawa R, Riley MB, Nilsson KPR, Kraus A, Caughey B, Iliff JJ, Vera DR, Esko JD, Sigurdson CJ. Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection. PLoS Pathog 2023; 19:e1011487. [PMID: 37747931 PMCID: PMC10586673 DOI: 10.1371/journal.ppat.1011487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 10/19/2023] [Accepted: 08/11/2023] [Indexed: 09/27/2023] Open
Abstract
Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a abundant extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase) from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of neuronal Ndst1- deficient mice, neuronal, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance.
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Affiliation(s)
| | - Adela Malik
- Department of Pathology, UC San Diego, La Jolla, California, United States of America
| | - Daniel R. Sandoval
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, California, United States of America
| | - Christopher Barback
- Department of Radiology, UC San Diego, La Jolla, California, United States of America
| | - Christina D. Orrù
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Heidi G. Standke
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Olivia R. Thomas
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Chrissa A. Dwyer
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, California, United States of America
| | - Donald P. Pizzo
- Department of Pathology, UC San Diego, La Jolla, California, United States of America
| | - Jaidev Bapat
- Department of Pathology, UC San Diego, La Jolla, California, United States of America
| | - Katrin Soldau
- Department of Pathology, UC San Diego, La Jolla, California, United States of America
| | - Ryotaro Ogawa
- Department of Radiology, UC San Diego, La Jolla, California, United States of America
| | - Mckenzie B. Riley
- Department of Neurology, University of Alabama, Birmingham, Alabama, United States of America
| | - K. Peter R. Nilsson
- Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden
| | - Allison Kraus
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Byron Caughey
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America
| | - Jeffrey J. Iliff
- VISN 20 NW Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington, United States of America
- Department of Psychiatry and Behavioral Science, Department of Neurology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - David R. Vera
- Department of Radiology, UC San Diego, La Jolla, California, United States of America
| | - Jeffrey D. Esko
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, California, United States of America
| | - Christina J. Sigurdson
- Department of Pathology, UC San Diego, La Jolla, California, United States of America
- Department of Medicine, UC San Diego, La Jolla, California, United States of America
- Department of Pathology, Microbiology, and Immunology, UC Davis, Davis, California, United States of America
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13
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Fujita K, Homma H, Jin M, Yoshioka Y, Jin X, Saito Y, Tanaka H, Okazawa H. Mutant α-synuclein propagates via the lymphatic system of the brain in the monomeric state. Cell Rep 2023; 42:112962. [PMID: 37591248 DOI: 10.1016/j.celrep.2023.112962] [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: 02/24/2023] [Revised: 06/30/2023] [Accepted: 07/24/2023] [Indexed: 08/19/2023] Open
Abstract
Prion-like protein propagation is considered a common pathogenic mechanism in neurodegenerative diseases. Here we investigate the in vivo propagation pattern and aggregation state of mutant α-synuclein by injecting adeno-associated viral (AAV)-α-synuclein-A53T-EGFP into the mouse olfactory cortex. Comparison of aggregation states in various brain regions at multiple time points after injection using western blot analyses shows that the monomeric state of the mutant/misfolded protein propagates to remote brain regions by 2 weeks and that the propagated proteins aggregate in situ after being incorporated into neurons. Moreover, injection of Alexa 488-labeled α-synuclein-A53T confirms the monomeric propagation at 2 weeks. Super-resolution microscopy shows that both α-synuclein-A53T proteins propagate via the lymphatic system, penetrate perineuronal nets, and reach the surface of neurons. Electron microscopy shows that the propagated mutant/misfolded monomer forms fibrils characteristic of Parkinson's disease after its incorporation into neurons. These findings suggest a mode of propagation different from that of aggregate-dependent propagation.
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Affiliation(s)
- Kyota Fujita
- Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Hidenori Homma
- Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Meihua Jin
- Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yuki Yoshioka
- Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Xiaocen Jin
- Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yuko Saito
- Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
| | - Hikari Tanaka
- Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Hitoshi Okazawa
- Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
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14
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Kell DB, Pretorius E. Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases? Biochem J 2023; 480:1217-1240. [PMID: 37584410 DOI: 10.1042/bcj20230241] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/03/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
It is now well established that the blood-clotting protein fibrinogen can polymerise into an anomalous form of fibrin that is amyloid in character; the resultant clots and microclots entrap many other molecules, stain with fluorogenic amyloid stains, are rather resistant to fibrinolysis, can block up microcapillaries, are implicated in a variety of diseases including Long COVID, and have been referred to as fibrinaloids. A necessary corollary of this anomalous polymerisation is the generation of novel epitopes in proteins that would normally be seen as 'self', and otherwise immunologically silent. The precise conformation of the resulting fibrinaloid clots (that, as with prions and classical amyloid proteins, can adopt multiple, stable conformations) must depend on the existing small molecules and metal ions that the fibrinogen may (and is some cases is known to) have bound before polymerisation. Any such novel epitopes, however, are likely to lead to the generation of autoantibodies. A convergent phenomenology, including distinct conformations and seeding of the anomalous form for initiation and propagation, is emerging to link knowledge in prions, prionoids, amyloids and now fibrinaloids. We here summarise the evidence for the above reasoning, which has substantial implications for our understanding of the genesis of autoimmunity (and the possible prevention thereof) based on the primary process of fibrinaloid formation.
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Affiliation(s)
- Douglas B Kell
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K
- The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Kemitorvet 200, 2800 Kgs Lyngby, Denmark
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch 7602, South Africa
| | - Etheresia Pretorius
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch 7602, South Africa
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15
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Acevedo S, Stewart AJ. Eco-evolutionary trade-offs in the dynamics of prion strain competition. Proc Biol Sci 2023; 290:20230905. [PMID: 37403499 PMCID: PMC10320356 DOI: 10.1098/rspb.2023.0905] [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: 04/18/2023] [Accepted: 06/07/2023] [Indexed: 07/06/2023] Open
Abstract
Prion and prion-like molecules are a type of self-replicating aggregate protein that have been implicated in a variety of neurodegenerative diseases. Over recent decades, the molecular dynamics of prions have been characterized both empirically and through mathematical models, providing insights into the epidemiology of prion diseases and the impact of prions on the evolution of cellular processes. At the same time, a variety of evidence indicates that prions are themselves capable of a form of evolution, in which changes to their structure that impact their rate of growth or fragmentation are replicated, making such changes subject to natural selection. Here we study the role of such selection in shaping the characteristics of prions under the nucleated polymerization model (NPM). We show that fragmentation rates evolve to an evolutionary stable value which balances rapid reproduction of PrPSc aggregates with the need to produce stable polymers. We further show that this evolved fragmentation rate differs in general from the rate that optimizes transmission between cells. We find that under the NPM, prions that are both evolutionary stable and optimized for transmission have a characteristic length of three times the critical length below which they become unstable. Finally, we study the dynamics of inter-cellular competition between strains, and show that the eco-evolutionary trade-off between intra- and inter-cellular competition favours coexistence.
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Affiliation(s)
- Saul Acevedo
- Department of Biology, University of Houston, Houston, TX, USA
| | - Alexander J. Stewart
- School of Mathematics and Statistics, University of St Andrews, St Andrews KY16 9SS, UK
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16
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Rangachari V. Biomolecular condensates - extant relics or evolving microcompartments? Commun Biol 2023; 6:656. [PMID: 37344557 PMCID: PMC10284869 DOI: 10.1038/s42003-023-04963-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/22/2023] [Indexed: 06/23/2023] Open
Abstract
Unprecedented discoveries during the past decade have unearthed the ubiquitous presence of biomolecular condensates (BCs) in diverse organisms and their involvement in a plethora of biological functions. A predominant number of BCs involve coacervation of RNA and proteins that demix from homogenous solutions by a process of phase separation well described by liquid-liquid phase separation (LLPS), which results in a phase with higher concentration and density from the bulk solution. BCs provide a simple and effective means to achieve reversible spatiotemporal control of cellular processes and adaptation to environmental stimuli in an energy-independent manner. The journey into the past of this phenomenon provides clues to the evolutionary origins of life itself. Here I assemble some current and historic discoveries on LLPS to contemplate whether BCs are extant biological hubs or evolving microcompartments. I conclude that BCs in biology could be extant as a phenomenon but are co-evolving as functionally and compositionally complex microcompartments in cells alongside the membrane-bound organelles.
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Affiliation(s)
- Vijayaraghavan Rangachari
- Department of Chemistry and Biochemistry, School of Mathematics and Natural Sciences and Center for Molecular and Cellular Biosciences, University of Southern Mississippi, Hattiesburg, MS, 39402, USA.
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17
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Avni A, Joshi A, Mukhopadhyay S. Hydrogen-Deuterium Exchange Vibrational Raman Spectroscopy Distinguishes Distinct Amyloid Polymorphs Comprising Altered Core Architecture. J Phys Chem Lett 2023:5592-5601. [PMID: 37307286 DOI: 10.1021/acs.jpclett.3c01086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Amyloid fibrils are ordered protein aggregates comprising a hydrogen-bonded central cross-β core displaying a structural diversity in their supramolecular packing arrangements within the core. Such an altered packing results in amyloid polymorphism that gives rise to morphological and biological strain diversities. Here, we show that vibrational Raman spectroscopy coupled with hydrogen/deuterium (H/D) exchange discerns the key structural features that are responsible for yielding diverse amyloid polymorphs. Such a noninvasive and label-free methodology allows us to structurally distinguish distinct amyloid polymorphs displaying altered hydrogen bonding and supramolecular packing within the cross-β structural motif. By using quantitative molecular fingerprinting and multivariate statistical analysis, we analyze key Raman bands for the protein backbone and side chains that allow us to capture the conformational heterogeneity and structural distributions within distinct amyloid polymorphs. Our results delineate the key molecular factors governing the structural diversity in amyloid polymorphs and can potentially simplify studying amyloid remodeling by small molecules.
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18
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Yoon J, Lee M, Park Y, Lee K, Shin S. In silico investigation of the structural stability as the origin of the pathogenicity of α-synuclein protofibrils. J Biomol Struct Dyn 2023; 41:14103-14115. [PMID: 37036430 DOI: 10.1080/07391102.2023.2199077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/31/2023] [Indexed: 04/11/2023]
Abstract
α-Synuclein is a presynaptic neuronal protein. The fibril form of α-synuclein is a major constituent of the intraneuronal inclusion called Lewy body, a characteristic hallmark of Parkinson's disease. Recent ssNMR and cryo-EM experiments of wild-type α-synuclein fibrils have shown polymorphism and observed two major polymorphs, rod and twister. To associate the cytotoxicity of α-synuclein fibrils with their structural features, it is essential to understand the origins of their structural stability. In this study, we performed molecular dynamics simulations of the two major polymorphs of wild-type α-synuclein fibrils. The predominance of specific fibril polymorphs was rationalized in terms of relative structural stability in aqueous environments, which was attributed to the cooperative contributions of various stabilizing features. The results of the simulations indicated that highly stable structures in aqueous environments could be maintained by the cooperation of compact sidechain packing in the hydrophobic core, backbone geometry of the maximal β-sheet content wrapping the hydrophobic core, and solvent-exposed sidechains with large fluctuations maximizing the solvation entropy. The paired structure of the two protofilaments provides additional stability, especially at the interface region, by forming steric zipper interactions and hiding the hydrophobic residues from exposure to water. The sidechain interaction analyses and pulling simulations showed that the rod polymorph has stronger sidechain interactions and exhibits higher dissociation energy than the twister polymorph. It is expected that our study will provide a basis for understanding the pathogenic behaviors of diverse amyloid strains in terms of their structural properties.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Jeseong Yoon
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - MinJun Lee
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - Yunsu Park
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - Kyunghee Lee
- Department of Chemistry, Sejong University, Seoul, Republic of Korea
| | - Seokmin Shin
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
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19
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Whitehead M, Yusoff S, Ahmad S, Schmidt L, Mayr M, Madine J, Middleton D, Shanahan CM. Vascular smooth muscle cell senescence accelerates medin aggregation via small extracellular vesicle secretion and extracellular matrix reorganization. Aging Cell 2023; 22:e13746. [PMID: 36433666 PMCID: PMC9924949 DOI: 10.1111/acel.13746] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 11/07/2022] [Accepted: 11/13/2022] [Indexed: 11/27/2022] Open
Abstract
Vascular amyloidosis, caused when peptide monomers aggregate into insoluble amyloid, is a prevalent age-associated pathology. Aortic medial amyloid (AMA) is the most common human amyloid and is composed of medin, a 50-amino acid peptide. Emerging evidence has implicated extracellular vesicles (EVs) as mediators of pathological amyloid accumulation in the extracellular matrix (ECM). To determine the mechanisms of AMA formation with age, we explored the impact of vascular smooth muscle cell (VSMC) senescence, EV secretion, and ECM remodeling on medin accumulation. Medin was detected in EVs secreted from primary VSMCs. Small, round medin aggregates colocalized with EV markers in decellularized ECM in vitro and medin was shown on the surface of EVs deposited in the ECM. Decreasing EV secretion with an inhibitor attenuated aggregation and deposition of medin in the ECM. Medin accumulation in the aortic wall of human subjects was strongly correlated with age and VSMC senescence increased EV secretion, increased EV medin loading and triggered deposition of fibril-like medin. Proteomic analysis showed VSMC senescence induced changes in EV cargo and ECM composition, which led to enhanced EV-ECM binding and accelerated medin aggregation. Abundance of the proteoglycan, HSPG2, was increased in the senescent ECM and colocalized with EVs and medin. Isolated EVs selectively bound to HSPG2 in the ECM and its knock-down decreased formation of fibril-like medin structures. These data identify VSMC-derived EVs and HSPG2 in the ECM as key mediators of medin accumulation, contributing to age-associated AMA development.
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Affiliation(s)
- Meredith Whitehead
- School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
| | - Syabira Yusoff
- School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
| | - Sadia Ahmad
- School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
| | - Lukas Schmidt
- School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
| | - Manuel Mayr
- School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
| | - Jillian Madine
- Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLondonUK
| | | | - Catherine M. Shanahan
- School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
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20
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Chen L, Yang J, Xu G, Wu Y. Potential Value and Application of Liquid Biopsy in Tumor, Neurodegeneration, and Muscle Degenerative Diseases. Methods Mol Biol 2023; 2695:317-335. [PMID: 37450129 DOI: 10.1007/978-1-0716-3346-5_22] [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] [Indexed: 07/18/2023]
Abstract
Liquid biopsy provides a promising alternative for the detection of disease-specific markers due to its superior noninvasive and original tissue representativeness. Liquid biopsies have a wide range of health and disease applications involving components ranging from circulating cells to acellular nucleic acid molecules and other metabolites. Here, we review the different components of liquid biopsy and investigate the most advanced noninvasive methods for detecting these components as well as their existing problems and trends. In particular, we emphasize the importance of analyzing liquid biopsy data from extracellular vesicles and small nucleic acids in neurological and muscle degeneration, with the aim of using this technique to enhance personalized healthcare. Although previous reviews have focused on cancer, this review mainly emphasizes the potential application of extracellular vesicles and microRNAs in liquid biopsy in neurodegeneration and muscle degeneration.
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Affiliation(s)
- Lin Chen
- Department of Health and Physical Education, Jianghan University, Wuhan, Hubei, People's Republic of China
| | - Jun Yang
- Jianghan University Library, Wuhan, Hubei, People's Republic of China
| | - Guodong Xu
- Department of Health and Physical Education, Jianghan University, Wuhan, Hubei, People's Republic of China
| | - Yuxiang Wu
- Department of Health and Physical Education, Jianghan University, Wuhan, Hubei, People's Republic of China.
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21
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Neupane S, De Cecco E, Aguzzi A. The Hidden Cell-to-Cell Trail of α-Synuclein Aggregates. J Mol Biol 2022:167930. [PMID: 36566800 DOI: 10.1016/j.jmb.2022.167930] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/10/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
The progressive accumulation of insoluble aggregates of the presynaptic protein alpha-synuclein (α-Syn) is a hallmark of neurodegenerative disorders including Parkinson's disease (PD), Multiple System Atrophy, and Dementia with Lewy Bodies, commonly referred to as synucleinopathies. Despite considerable progress on the structural biology of these aggregates, the molecular mechanisms mediating their cell-to-cell transmission, propagation, and neurotoxicity remain only partially understood. Numerous studies have highlighted the stereotypical spatiotemporal spreading of pathological α-Syn aggregates across different tissues and anatomically connected brain regions over time. Experimental evidence from various cellular and animal models indicate that α-Syn transfer occurs in two defined steps: the release of pathogenic α-Syn species from infected cells, and their uptake via passive or active endocytic pathways. Once α-Syn aggregates have been internalized, little is known about what drives their toxicity or how they interact with the endogenous protein to promote its misfolding and subsequent aggregation. Similarly, unknown genetic factors modulate different cellular responses to the aggregation and accumulation of pathogenic α-Syn species. Here we discuss the current understanding of the molecular phenomena associated with the intercellular spreading of pathogenic α-Syn seeds and summarize the evidence supporting the transmission hypothesis. Understanding the molecular mechanisms involved in α-Syn aggregates transmission is essential to develop novel targeted therapeutics against PD and related synucleinopathies.
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Affiliation(s)
- Sandesh Neupane
- Institute of Neuropathology, University Hospital of Zurich, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland. https://twitter.com/neuron_sandesh
| | - Elena De Cecco
- Institute of Neuropathology, University Hospital of Zurich, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
| | - Adriano Aguzzi
- Institute of Neuropathology, University Hospital of Zurich, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
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22
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Dadgar-Kiani E, Bieri G, Melki R, Gitler AD, Lee JH. Mesoscale connections and gene expression empower whole-brain modeling of α-synuclein spread, aggregation, and decay dynamics. Cell Rep 2022; 41:111631. [PMID: 36351406 PMCID: PMC10840492 DOI: 10.1016/j.celrep.2022.111631] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/19/2022] [Accepted: 10/18/2022] [Indexed: 11/11/2022] Open
Abstract
An emerging view regarding neurodegenerative diseases is that discreet seeding of misfolded proteins leads to widespread pathology. However, the mechanisms by which misfolded proteins seed distinct brain regions and cause differential whole-brain pathology remain elusive. We used whole-brain tissue clearing and high-resolution imaging to longitudinally map pathology in an α-synuclein pre-formed fibril injection model of Parkinson's disease. Cleared brains at different time points of disease progression were quantitatively segmented and registered to a standardized atlas, revealing distinct phases of spreading and decline. We then fit a computational model with parameters that represent α-synuclein pathology spreading, aggregation, decay, and gene expression pattern to this longitudinal dataset. Remarkably, our model can generalize to predicting α-synuclein spreading patterns from several distinct brain regions and can even estimate their origins. This model empowers mechanistic understanding and accurate prediction of disease progression, paving the way for the development and testing of therapeutic interventions.
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Affiliation(s)
- Ehsan Dadgar-Kiani
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
| | - Gregor Bieri
- Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Ronald Melki
- Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, 92265 Fontenay-Aux-Roses, France
| | - Aaron D Gitler
- Department of Genetics, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
| | - Jin Hyung Lee
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
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23
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Microglial Extracellular Vesicles as Modulators of Brain Microenvironment in Glioma. Int J Mol Sci 2022; 23:ijms232113165. [PMID: 36361947 PMCID: PMC9656645 DOI: 10.3390/ijms232113165] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 11/22/2022] Open
Abstract
Microglial cells represent the resident immune elements of the central nervous system, where they exert constant monitoring and contribute to preserving neuronal activity and function. In the context of glioblastoma (GBM), a common type of tumor originating in the brain, microglial cells deeply modify their phenotype, lose their homeostatic functions, invade the tumoral mass and support the growth and further invasion of the tumoral cells into the surrounding brain parenchyma. These modifications are, at least in part, induced by bidirectional communication among microglial and tumoral cells through the release of soluble molecules and extracellular vesicles (EVs). EVs produced by GBM and microglial cells transfer different kinds of biological information to receiving cells, deeply modifying their phenotype and activity and could represent important diagnostic markers and therapeutic targets. Recent evidence demonstrates that in GBM, microglial-derived EVs contribute to the immune suppression of the tumor microenvironment (TME), thus favoring GBM immune escape. In this review, we report the current knowledge on EV formation, biogenesis, cargo and functions, with a focus on the effects of microglia-derived EVs in GBM. What clearly emerges from this analysis is that we are at the beginning of a full understanding of the complete picture of the biological effects of microglial-derived EVs and that further investigations using multidisciplinary approaches are necessary to validate their use in GBM diagnosis and therapy.
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24
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Li J, Guo M, Chen L, Chen Z, Fu Y, Chen Y. p53 amyloid aggregation in cancer: function, mechanism, and therapy. Exp Hematol Oncol 2022; 11:66. [PMID: 36171607 PMCID: PMC9520902 DOI: 10.1186/s40164-022-00317-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 09/13/2022] [Indexed: 11/28/2022] Open
Abstract
Similar to neurodegenerative diseases, the concept that tumors are prion like diseases has been proposed in recent years. p53, the most well-known tumor suppressor, has been extensively studied for its expression, mutation, and function in various tumors. Currently, an interesting phenomenon of p53 prion-like aggregation has been found in several tumors, and studies have found that its pathological aggregation may lead to functional alterations and ultimately affect tumor progression. It has been demonstrated that the mechanism of p53 aggregation involves its mutation, domains, isoform, etc. In addition to p53 itself, some other factors, including Zn2+ concentration, pH, temperature and chaperone abnormalities, can also contribute to p53 aggregation. Although there are some studies about the mechanism and role of p53 aggregation and amyloidosis in tumors, there still exist some controversies. In this paper, we review the mechanism of p53 amyloid fibril structure and discuss the characteristics and effects of p53 amyloid aggregation, as well as the pathogenic mechanism leading to the occurrence of aggregation in tumors. Finally, we summarize the various inhibitors targeting p53 aggregation and prion-like behavior. In conclusion, a comprehensive understanding of p53 aggregation can expand our understanding of the causes leading its loss of physiological function and that targeting p53 aggregation might be a promising therapeutic strategy for tumor therapy.
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Affiliation(s)
- Jingzhi Li
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.,Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Ming Guo
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Lin Chen
- Molecular and Computational Biology Program, Department of Biological Sciences and Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA
| | - Zhuchu Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Ying Fu
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. .,Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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25
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Tao DL, Zhao SS, Chen JM, Chen X, Yang X, Song JK, Liu Q, Zhao GH. Neospora caninum infection induced mitochondrial dysfunction in caprine endometrial epithelial cells via downregulating SIRT1. Parasit Vectors 2022; 15:274. [PMID: 35915458 PMCID: PMC9344697 DOI: 10.1186/s13071-022-05406-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 07/19/2022] [Indexed: 02/07/2023] Open
Abstract
Background Infection of Neospora caninum, an important obligate intracellular protozoan parasite, causes reproductive dysfunctions (e.g. abortions) in ruminants (e.g. cattle, sheep and goats), leading to serious economic losses of livestock worldwide, but the pathogenic mechanisms of N. caninum are poorly understood. Mitochondrial dysfunction has been reported to be closely associated with pathogenesis of many infectious diseases. However, the effect of N. caninum infection on the mitochondrial function of hosts remains unclear. Methods The effects of N. caninum infection on mitochondrial dysfunction in caprine endometrial epithelial cells (EECs), including intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) contents, mitochondrial DNA (mtDNA) copy numbers and ultrastructure of mitochondria, were studied by using JC-1, DCFH-DA, ATP assay kits, quantitative real-time polymerase chain reaction (RT-qPCR) and transmission electron microscopy, respectively, and the regulatory roles of sirtuin 1 (SIRT1) on mitochondrial dysfunction, autophagy and N. caninum propagation in caprine EECs were investigated by using two drugs, namely resveratrol (an activator of SIRT1) and Ex 527 (an inhibitor of SIRT1). Results The current study found that N. caninum infection induced mitochondrial dysfunction of caprine EECs, including accumulation of intracellular ROS, significant reductions of MMP, ATP contents, mtDNA copy numbers and damaged ultrastructure of mitochondria. Downregulated expression of SIRT1 was also detected in caprine EECs infected with N. caninum. Treatments using resveratrol and Ex 527 to caprine EECs showed that dysregulation of SIRT1 significantly reversed mitochondrial dysfunction of cells caused by N. caninum infection. Furthermore, using resveratrol and Ex 527, SIRT1 expression was found to be negatively associated with autophagy induced by N. caninum infection in caprine EECs, and the intracellular propagation of N. caninum tachyzoites in caprine EECs was negatively affected by SIRT1 expression. Conclusions These results indicated that N. caninum infection induced mitochondrial dysfunction by downregulating SIRT1, and downregulation of SIRT1 promoted cell autophagy and intracellular proliferation of N. caninum tachyzoites in caprine EECs. The findings suggested a potential role of SIRT1 as a target to develop control strategies against N. caninum infection. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13071-022-05406-4.
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Affiliation(s)
- De-Liang Tao
- Department of Parasitology, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Shan-Shan Zhao
- Department of Parasitology, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Jin-Ming Chen
- Department of Parasitology, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Xi Chen
- Department of Parasitology, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Xin Yang
- Department of Parasitology, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Jun-Ke Song
- Department of Parasitology, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China
| | - Qun Liu
- National Animal Protozoa Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
| | - Guang-Hui Zhao
- Department of Parasitology, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China.
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26
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Sakunthala A, Datta D, Navalkar A, Gadhe L, Kadu P, Patel K, Mehra S, Kumar R, Chatterjee D, Devi J, Sengupta K, Padinhateeri R, Maji SK. Direct Demonstration of Seed Size-Dependent α-Synuclein Amyloid Amplification. J Phys Chem Lett 2022; 13:6427-6438. [PMID: 35816132 DOI: 10.1021/acs.jpclett.2c01650] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The size of amyloid seeds is known to modulate their autocatalytic amplification and cellular toxicity. However, the seed size-dependent secondary nucleation mechanism, toxicity, and disease-associated biological processes mediated by α-synuclein (α-Syn) fibrils are largely unknown. Using the cellular model and in vitro reconstitution, we showed that the size of α-Syn fibril seeds dictates not only their cellular internalization and associated cell death but also the distinct mechanisms of fibril amplification pathways involved in the pathological conformational change of α-Syn. Specifically, small fibril seeds showed elongation possibly through monomer addition at the fibril termini, whereas longer fibrils template the fibril amplification by surface-mediated nucleation as demonstrated by super-resolution microscopy. The distinct mechanism of fibril amplification and cellular uptake along with toxicity suggest that breakage of fibrils into seeds of different sizes determines the underlying pathological outcome of synucleinopathies.
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Affiliation(s)
- Arunima Sakunthala
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Debalina Datta
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Ambuja Navalkar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Laxmikant Gadhe
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Pradeep Kadu
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Komal Patel
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Surabhi Mehra
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Rakesh Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Debdeep Chatterjee
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Jyoti Devi
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Kundan Sengupta
- Chromosome Biology Lab, Indian Institute of Science Education and Research, Pune 411008, India
| | - Ranjith Padinhateeri
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Samir K Maji
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
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27
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Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice. Acta Neuropathol 2022; 143:663-685. [PMID: 35488930 DOI: 10.1007/s00401-022-02425-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 12/22/2022]
Abstract
α-synuclein (αSyn) is an intrinsically disordered protein which can undergo structural transformations, resulting in the formation of stable, insoluble fibrils. αSyn amyloid-type nucleation can be induced by misfolded 'seeds' serving as a conformational template, tantamount to the prion-like mechanism. Accumulation of αSyn inclusions is a key feature of dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), and are found as additional pathology in Alzheimer's disease (AD) such as AD with amygdala predominant Lewy bodies (AD/ALB). While these disorders accumulate the same pathological protein, they exhibit heterogeneity in clinical and histological features; however, the mechanism(s) underlying this variability remains elusive. Accruing data from human autopsy studies, animal inoculation modeling, and in vitro characterization experiments, have lent credence to the hypothesis that conformational polymorphism of the αSyn amyloid-type fibril structure results in distinct "strains" with categorical infectivity traits. Herein, we directly compare the seeding abilities and outcome of human brain lysates from these diseases, as well as recombinant preformed human αSyn fibrils by the intracerebral inoculation of transgenic mice overexpressing either human wild-type αSyn or human αSyn with the familial A53T mutation. Our study has revealed that the initiating inoculum heavily dictates the phenotypic and pathological course of disease. Interestingly, we have also established relevant host-dependent distinctions between propagation profiles, including burden and spread of inclusion pathology throughout the neuroaxis, as well as severity of neurological symptoms. These findings provide compelling evidence supporting the hypothesis that diverse prion-type conformers may explain the variability seen in synucleinopathies.
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28
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Plattner H. Ciliate Research. From Myth to Trendsetting Science. J Eukaryot Microbiol 2022; 69:e12926. [PMID: 35608570 DOI: 10.1111/jeu.12926] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/18/2022] [Accepted: 05/18/2022] [Indexed: 11/28/2022]
Abstract
This special issue of the Journal of Eukaryotic Microbiology (JEM) summarizes achievements obtained by generations of researchers with ciliates in widely different disciplines. In fact, ciliates range among the first cells seen under the microscope centuries ago. Their beauty made them an object of scientia amabilis and their manifold reactions made them attractive for college experiments and finally challenged causal analyses at the cellular level. Some of this work was honored by a Nobel Prize. Some observations yielded a baseline for additional novel discoveries, occasionally facilitated by specific properties of some ciliates. This also offers some advantage in the exploration of closely related parasites (malaria). Articles contributed here by colleagues from all over the world encompass a broad spectrum of ciliate life, from genetics to evolution, from molecular cell biology to ecology, from intercellular signaling to epigenetics etc. This introductory chapter, largely based on my personal perception, aims at integrating work presented in this special issue of JEM into a broader historical context up to current research.
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29
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Thackray AM, Lam B, McNulty EE, Nalls AV, Mathiason CK, Magadi SS, Jackson WS, Andréoletti O, Marrero-Winkens C, Schätzl H, Bujdoso R. Clearance of variant Creutzfeldt-Jakob disease prions in vivo by the Hsp70 disaggregase system. Brain 2022; 145:3236-3249. [PMID: 35446941 PMCID: PMC9473358 DOI: 10.1093/brain/awac144] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/10/2022] [Accepted: 03/30/2022] [Indexed: 11/13/2022] Open
Abstract
The metazoan Hsp70 disaggregase protects neurons from proteotoxicity that arises from the accumulation of misfolded protein aggregates. Hsp70 and its co-chaperones disassemble and extract polypeptides from protein aggregates for refolding or degradation. The effectiveness of the chaperone system decreases with age and leads to accumulation rather than removal of neurotoxic protein aggregates. Therapeutic enhancement of the Hsp70 protein disassembly machinery is proposed to counter late-onset protein misfolding neurodegenerative disease that may arise. In the context of prion disease, it is not known whether stimulation of protein aggregate disassembly paradoxically leads to enhanced formation of seeding competent species of disease-specific proteins and acceleration of neurodegenerative disease. Here we have tested the hypothesis that modulation of Hsp70 disaggregase activity perturbs mammalian prion-induced neurotoxicity and prion seeding activity. To do so we used prion protein (PrP) transgenic Drosophila that authentically replicate mammalian prions. RNASeq identified that Hsp70, DnaJ-1 and Hsp110 gene expression was downregulated in prion-exposed PrP Drosophila. We demonstrated that RNAi knockdown of Hsp110 or DnaJ-1 gene expression in variant Creutzfeldt–Jakob disease prion-exposed human PrP Drosophila enhanced neurotoxicity, whereas overexpression mitigated toxicity. Strikingly, prion seeding activity in variant Creutzfeldt–Jakob disease prion-exposed human PrP Drosophila was ablated or reduced by Hsp110 or DnaJ-1 overexpression, respectively. Similar effects were seen in scrapie prion-exposed ovine PrP Drosophila with modified Hsp110 or DnaJ-1 gene expression. These unique observations show that the metazoan Hsp70 disaggregase facilitates the clearance of mammalian prions and that its enhanced activity is a potential therapeutic strategy for human prion disease.
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Affiliation(s)
- Alana M Thackray
- University of Cambridge, Department of Veterinary Medicine, Madingley Road, Cambridge, CB3 0ES, UK
| | - Brian Lam
- Medical Research Council Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Erin E McNulty
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Amy V Nalls
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Candace K Mathiason
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Srivathsa Subramanya Magadi
- Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
| | - Walker S Jackson
- Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
| | - Olivier Andréoletti
- UMR INRA ENVT 1225 -Hôtes-Agents Pathogènes, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, 31076 Toulouse, France
| | - Cristóbal Marrero-Winkens
- Calgary Prion Research Unit, Faculty of Veterinary Medicine, University of Calgary TRW 2D10, 3280 Hospital Drive NW, Calgary, AB, Canada T2N 4Z6
| | - Hermann Schätzl
- Calgary Prion Research Unit, Faculty of Veterinary Medicine, University of Calgary TRW 2D10, 3280 Hospital Drive NW, Calgary, AB, Canada T2N 4Z6
| | - Raymond Bujdoso
- University of Cambridge, Department of Veterinary Medicine, Madingley Road, Cambridge, CB3 0ES, UK
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Marino M, Holt MG. AAV Vector-Mediated Antibody Delivery (A-MAD) in the Central Nervous System. Front Neurol 2022; 13:870799. [PMID: 35493843 PMCID: PMC9039256 DOI: 10.3389/fneur.2022.870799] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
In the last four decades, monoclonal antibodies and their derivatives have emerged as a powerful class of therapeutics, largely due to their exquisite targeting specificity. Several clinical areas, most notably oncology and autoimmune disorders, have seen the successful introduction of monoclonal-based therapeutics. However, their adoption for treatment of Central Nervous System diseases has been comparatively slow, largely due to issues of efficient delivery resulting from limited permeability of the Blood Brain Barrier. Nevertheless, CNS diseases are becoming increasingly prevalent as societies age, accounting for ~6.5 million fatalities worldwide per year. Therefore, harnessing the full therapeutic potential of monoclonal antibodies (and their derivatives) in this clinical area has become a priority. Adeno-associated virus-based vectors (AAVs) are a potential solution to this problem. Preclinical studies have shown that AAV vector-mediated antibody delivery provides protection against a broad range of peripheral diseases, such as the human immunodeficiency virus (HIV), influenza and malaria. The parallel identification and optimization of AAV vector platforms which cross the Blood Brain Barrier with high efficiency, widely transducing the Central Nervous System and allowing high levels of local transgene production, has now opened a number of interesting scenarios for the development of AAV vector-mediated antibody delivery strategies to target Central Nervous System proteinopathies.
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Affiliation(s)
- Marika Marino
- Laboratory of Glia Biology, VIB-KU Leuven, Center for Brain & Disease Research, Leuven, Belgium
- Department of Neurosciences, KU Leuven, Leuven, Belgium
| | - Matthew G. Holt
- Laboratory of Glia Biology, VIB-KU Leuven, Center for Brain & Disease Research, Leuven, Belgium
- Department of Neurosciences, KU Leuven, Leuven, Belgium
- Leuven Brain Institute, Leuven, Belgium
- Synapse Biology Group, Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- *Correspondence: Matthew G. Holt
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Alzheimer's disease protease-containing plasma extracellular vesicles transfer to the hippocampus via the choroid plexus. EBioMedicine 2022; 77:103903. [PMID: 35220044 PMCID: PMC8889140 DOI: 10.1016/j.ebiom.2022.103903] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 02/10/2022] [Accepted: 02/10/2022] [Indexed: 12/15/2022] Open
Abstract
Background Plasma extracellular vesicles (pEV) can harbor a diverse array of factors including active proteases and the amyloid-precursor-protein (APP) cleavage product Aβ, involved in plaque formation in Alzheimer`s diseases (AD). A potential role of such vesicles in AD pathology is unexplored. Methods In a case-control study of randomly selected patients with AD and other neurological diseases (n = 14), and healthy controls (n = 7), we systematically analyzed the content of pEV, using different assay systems. In addition, we determined their entry path into brain tissue, employing animal (mice) injection experiments with ex vivo generated EV that were similar to AD-pEV, followed by multi antigen analysis (MAA) of brain tissue (n = 4 per condition). The results were compared with an IHC staining of human brain tissue in a small cohort of AD patients (n = 3) and controls with no neurodegenerative diseases (n = 3). Findings We show that pEV levels are considerably upregulated in AD patients. Besides numerous inflammatory effectors, AD-pEV contained α-, β- and γ-secretases, able to cleave APP in in target cells. In vitro generated EV with similar characteristics as AD-pEV accumulated in the choroid plexus (CP) of injected animals and reached primarily hippocampal neurons. Corroborating findings were made in human brain samples. An inhibitor of hyaluronic-acid-synthetase (HAS) blocked uploading of proteases and Hyaluronan onto EV in vitro and abolished CP targeting in animal injection experiments. Interpretation We conclude that protease-containing pEV could be part of a communication axis between the periphery and the brain that could be become detrimental depending on pEV concentration and duration of target cell impact.
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Biochemical and subcellular characterization of a squid hnRNPA/B-like protein 2 in osmotic stress activated cells reflects molecular properties conserved in this protein family. Mol Biol Rep 2022; 49:4257-4268. [PMID: 35192131 DOI: 10.1007/s11033-022-07260-0] [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: 08/21/2021] [Accepted: 02/10/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND We have identified endogenous p65 to be an SDS-stable dimer protein composed of ~ 37 kDa hnRNPA/B-like subunits. We have investigated molecular properties involved in the stability of dimeric form, and their regulation in the transition between monomeric and dimeric forms of hnRNPA/B-like protein 2. We also investigated a cellular property conserved between squid hnRNPA/B-like protein 2 and human hnRNPA1 protein in a neuronal context. METHODS AND RESULTS Here we show biochemical properties of a recombinant hnRNPA/B-like protein 2 (rP2) in vitro experiments, as one of p65 subunit. We found that interaction between rP2 and RNA molecules interfered with the dynamics of rP2 dimers formation, involved in disulfide bonds and/or postranslational alterations in distinct stage of SDS-stable dimers formation. In addition, we have performed immunofluorescence in SH-SY5Y cells and observed that the pEGFP-P2 fusion protein was expressed in the nucleus, similar to what is observed for human hnRNPA1 protein. CONCLUSION Our results reinforce the idea that p65 is an SDS-stable dimer. Thus, a deeper understanding between monomeric and dimeric transition dynamic is critical into evolution of several neurodegenerative disease.
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Semerdzhiev SA, Fakhree MAA, Segers-Nolten I, Blum C, Claessens MMAE. Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation. ACS Chem Neurosci 2022; 13:143-150. [PMID: 34860005 PMCID: PMC8739828 DOI: 10.1021/acschemneuro.1c00666] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
![]()
First cases that
point at a correlation between SARS-CoV-2 infections
and the development of Parkinson’s disease (PD) have been reported.
Currently, it is unclear if there is also a direct causal link between
these diseases. To obtain first insights into a possible molecular
relation between viral infections and the aggregation of α-synuclein
protein into amyloid fibrils characteristic for PD, we investigated
the effect of the presence of SARS-CoV-2 proteins on α-synuclein
aggregation. We show, in test tube experiments, that SARS-CoV-2 spike
protein (S-protein) has no effect on α-synuclein aggregation,
while SARS-CoV-2 nucleocapsid protein (N-protein) considerably speeds
up the aggregation process. We observe the formation of multiprotein
complexes and eventually amyloid fibrils. Microinjection of N-protein
in SH-SY5Y cells disturbed the α-synuclein proteostasis and
increased cell death. Our results point toward direct interactions
between the N-protein of SARS-CoV-2 and α-synuclein as molecular
basis for the observed correlation between SARS-CoV-2 infections and
Parkinsonism.
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Affiliation(s)
- Slav A. Semerdzhiev
- Nanobiophysics, MESA+ Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands
| | - Mohammad A. A. Fakhree
- Nanobiophysics, MESA+ Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands
| | - Ine Segers-Nolten
- Nanobiophysics, MESA+ Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands
| | - Christian Blum
- Nanobiophysics, MESA+ Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands
| | - Mireille M. A. E. Claessens
- Nanobiophysics, MESA+ Institute for Nanotechnology, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands
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Galzitskaya O, Selivanova O, Dzhus U, Marchenkov V, Suvorina MY, Surin A. Influence of Chaperones on Amyloid Formation of Аβ Peptide. Curr Protein Pept Sci 2022; 23:44-51. [DOI: 10.2174/1389203723666220127152545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 11/22/2022]
Abstract
Background:
An extensive study of the folding and stability of proteins and their complexes
has revealed a number of problems and questions that need to be answered. One of them is the
effect of chaperones on the process of fibrillation of various proteins and peptides.
Methods:
We studied the effect of molecular chaperones, such as GroEL and α-crystallin, on the fibrillogenesis
of the Aβ(1-42) peptide using electron microscopy and surface plasmon resonance.
Results:
Recombinant GroEL and Aβ(1-42) were isolated and purified. It was shown that the assembly
of GroEL occurs without the addition of magnesium and potassium ions, as is commonly believed.
According to the electron microscopy results, GroEL insignificantly affects the fibrillogenesis of the
Aβ(1-42) peptide, while α-crystallin prevents the elongation of the Aβ(1-42) peptide fibrils. We have
demonstrated that GroEL interacts nonspecifically with Aβ(1-42), while α-crystallin does not interact
with Aβ(1-42) at all using surface plasmon resonance.
Conclusion:
The data obtained will help us understand the process of amyloid formation and the effect
of various components on it.
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Affiliation(s)
- O.V. Galzitskaya
- Institute of Protein Research, Russian Academy of Sciences, 4 Institutskaya str., Pushchino, Moscow Region, 142290,
Russia
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino Moscow
Region, Russia
| | - O.M. Selivanova
- Institute of Protein Research, Russian Academy of Sciences, 4 Institutskaya str., Pushchino, Moscow Region, 142290,
Russia
| | - U.F. Dzhus
- Institute of Protein Research, Russian Academy of Sciences, 4 Institutskaya str., Pushchino, Moscow Region, 142290,
Russia
| | - V.V. Marchenkov
- Institute of Protein Research, Russian Academy of Sciences, 4 Institutskaya str., Pushchino, Moscow Region, 142290,
Russia
| | - M. Yu. Suvorina
- Institute of Protein Research, Russian Academy of Sciences, 4 Institutskaya str., Pushchino, Moscow Region, 142290,
Russia
| | - A.K. Surin
- Institute of Protein Research, Russian Academy of Sciences, 4 Institutskaya str., Pushchino, Moscow Region, 142290,
Russia
- State Research Center for Applied Microbiology and Biotechnology, 142279 Obolensk Moscow Region, Russia
- The Branch of the Institute of Bioorganic Chemistry, Russian Academy of Sciences, 142290 Pushchino
Moscow Region, Russia
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35
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Patel H, Martinez P, Perkins A, Taylor X, Jury N, McKinzie D, Lasagna-Reeves CA. Pathological tau and reactive astrogliosis are associated with distinct functional deficits in a mouse model of tauopathy. Neurobiol Aging 2022; 109:52-63. [PMID: 34655981 PMCID: PMC8671336 DOI: 10.1016/j.neurobiolaging.2021.09.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 08/12/2021] [Accepted: 09/05/2021] [Indexed: 01/03/2023]
Abstract
Pathological aggregation of tau and neuroinflammatory changes mark the clinical course of Alzheimer's disease and related tauopathies. To understand the correlation between these pathological hallmarks and functional deficits, we assessed behavioral and physiological deficits in the PS19 mouse model, a broadly utilized model of tauopathy. At 9 months, PS19 mice have characteristic hyperactive behavior, a decline in motor strength, and deterioration in physiological conditions marked by lower body temperature, reduced body weight, and an increase in measures of frailty. Correlation of these deficits with different pathological hallmarks revealed that pathological tau species, characterized by soluble p-tau species, and tau seeding bioactivity correlated with impairment in grip strength and thermal regulation. On the other hand, astrocyte reactivity showed a positive correlation with the hyperactive behavior of the PS19 mice. These results suggest that a diverse spectrum of soluble pathological tau species could be responsible for different symptoms and that neuroinflammation could contribute to functional deficits independently from tau pathology. These observations enhance the necessity of a multi-targeted approach for the treatment of neurodegenerative tauopathies.
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Affiliation(s)
- Henika Patel
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Pablo Martinez
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Abigail Perkins
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Xavier Taylor
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Nur Jury
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - David McKinzie
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Cristian A. Lasagna-Reeves
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA,Corresponding author: Cristian A. Lasagna-Reeves, Ph.D., Indiana University School of Medicine, The Stark Neurosciences Research Institute, Neurosciences Research Building 214G, 320 West 15th Street, Indianapolis, IN, 46202, Office: (317) 274-7830,
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36
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Aprile FA, Temussi PA, Pastore A. Man does not live by intrinsically unstructured proteins alone: The role of structured regions in aggregation. Bioessays 2021; 43:e2100178. [PMID: 34674273 DOI: 10.1002/bies.202100178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/11/2021] [Accepted: 09/13/2021] [Indexed: 12/30/2022]
Abstract
Protein misfolding is a topic that is of primary interest both in biology and medicine because of its impact on fundamental processes and disease. In this review, we revisit the concept of protein misfolding and discuss how the field has evolved from the study of globular folded proteins to focusing mainly on intrinsically unstructured and often disordered regions. We argue that this shift of paradigm reflects the more recent realisation that misfolding may not only be an adverse event, as originally considered, but also may fulfil a basic biological need to compartmentalise the cell with transient reversible granules. We nevertheless provide examples in which structure is an important component of a much more complex aggregation behaviour that involves both structured and unstructured regions of a protein. We thus suggest that a more comprehensive evaluation of the mechanisms that lead to aggregation might be necessary.
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Affiliation(s)
- Francesco A Aprile
- Department of Chemistry, Imperial College London, White City Campus, 82 Wood Lane, London, W12 0BZ, UK
| | - Piero Andrea Temussi
- UK Dementia Research Institute at the Maurice Wohl Institute of King's College London, London, UK
| | - Annalisa Pastore
- UK Dementia Research Institute at the Maurice Wohl Institute of King's College London, London, UK
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37
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Fassler JS, Skuodas S, Weeks DL, Phillips BT. Protein Aggregation and Disaggregation in Cells and Development. J Mol Biol 2021; 433:167215. [PMID: 34450138 PMCID: PMC8530975 DOI: 10.1016/j.jmb.2021.167215] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/01/2021] [Accepted: 08/18/2021] [Indexed: 12/12/2022]
Abstract
Protein aggregation is a feature of numerous neurodegenerative diseases. However, regulated, often reversible, formation of protein aggregates, also known as condensates, helps control a wide range of cellular activities including stress response, gene expression, memory, cell development and differentiation. This review presents examples of aggregates found in biological systems, how they are used, and cellular strategies that control aggregation and disaggregation. We include features of the aggregating proteins themselves, environmental factors, co-aggregates, post-translational modifications and well-known aggregation-directed activities that influence their formation, material state, stability and dissolution. We highlight the emerging roles of biomolecular condensates in early animal development, and disaggregation processing proteins that have recently been shown to play key roles in gametogenesis and embryogenesis.
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Affiliation(s)
- Jan S Fassler
- Department of Biology, University of Iowa, Iowa City, IA 52242, United States.
| | - Sydney Skuodas
- Department of Biology, University of Iowa, Iowa City, IA 52242, United States. https://twitter.com/@sskuodas
| | - Daniel L Weeks
- Department of Biochemistry, University of Iowa, Iowa City, IA 52242, United States
| | - Bryan T Phillips
- Department of Biology, University of Iowa, Iowa City, IA 52242, United States. https://twitter.com/@bt4phillips
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38
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Mehra S, Gadhe L, Bera R, Sawner AS, Maji SK. Structural and Functional Insights into α-Synuclein Fibril Polymorphism. Biomolecules 2021; 11:1419. [PMID: 34680054 PMCID: PMC8533119 DOI: 10.3390/biom11101419] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/21/2021] [Accepted: 09/23/2021] [Indexed: 12/21/2022] Open
Abstract
Abnormal accumulation of aggregated α-synuclein (α-Syn) is seen in a variety of neurodegenerative diseases, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), Parkinson's disease dementia (PDD), and even subsets of Alzheimer's disease (AD) showing Lewy-body-like pathology. These synucleinopathies exhibit differences in their clinical and pathological representations, reminiscent of prion disorders. Emerging evidence suggests that α-Syn self-assembles and polymerizes into conformationally diverse polymorphs in vitro and in vivo, similar to prions. These α-Syn polymorphs arising from the same precursor protein may exhibit strain-specific biochemical properties and the ability to induce distinct pathological phenotypes upon their inoculation in animal models. In this review, we discuss clinical and pathological variability in synucleinopathies and several aspects of α-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains. The current review sheds light on the recent advances in delineating the structure-pathogenic relationship of α-Syn and how diverse α-Syn molecular polymorphs contribute to the existing clinical heterogeneity in synucleinopathies.
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Affiliation(s)
- Surabhi Mehra
- Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India; (L.G.); (R.B.); (A.S.S.)
| | | | | | | | - Samir K. Maji
- Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India; (L.G.); (R.B.); (A.S.S.)
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39
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Chen QY, Wen T, Wu P, Jia R, Zhang R, Dang J. Exosomal Proteins and miRNAs as Mediators of Amyotrophic Lateral Sclerosis. Front Cell Dev Biol 2021; 9:718803. [PMID: 34568332 PMCID: PMC8461026 DOI: 10.3389/fcell.2021.718803] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/13/2021] [Indexed: 12/14/2022] Open
Abstract
Recent advances in the neurobiology and neurogenerative diseases have attracted growing interest in exosomes and their ability to carry and propagate active biomolecules as a means to reprogram recipient cells. Alterations in exosomal protein content and nucleic acid profiles found in human biological fluids have been correlated with various diseases including amyotrophic lateral sclerosis (ALS). In ALS pathogenesis, these lipid-bound nanoscale vesicles have emerged as valuable candidates for diagnostic biomarkers. Moreover, their capacity to spread misfolded proteins and functional non-coding RNAs to interconnected neuronal cells make them putative mediators for the progressive motor degeneration found remarkably apparent in ALS. This review outlines current knowledge concerning the biogenesis, heterogeneity, and function of exosomes in the brain as well as a comprehensive probe of currently available literature on ALS-related exosomal proteins and microRNAs. Lastly, with the rapid development of employing nanoparticles for drug delivery, we explore the therapeutic potentials of exosomes as well as underlying limitations in current isolation and detection methodologies.
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Affiliation(s)
- Qiao Yi Chen
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
| | - Ting Wen
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
| | - Peng Wu
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
| | - Rui Jia
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ronghua Zhang
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jingxia Dang
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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40
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Abstract
Prion diseases are neurodegenerative disorders caused by conformational conversion of the cellular prion protein (PrPC) into scrapie prion protein (PrPSc). As the main component of prion, PrPSc acts as an infectious template that recruits and converts normal cellular PrPC into its pathogenic, misfolded isoform. Intriguingly, the phenomenon of prionoid, or prion-like, spread has also been observed in many other disease-associated proteins, such as amyloid β (Aβ), tau and α-synuclein. This Cell Science at a Glance and the accompanying poster highlight recently described physiological roles of prion protein and the advanced understanding of pathogenesis of prion disease they have afforded. Importantly, prion protein may also be involved in the pathogenesis of other neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therapeutic studies of prion disease have also exploited novel strategies to combat these devastating diseases. Future studies on prion protein and prion disease will deepen our understanding of the pathogenesis of a broad spectrum of neurodegenerative conditions.
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Affiliation(s)
- Caihong Zhu
- School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Adriano Aguzzi
- Institute of Neuropathology, University Hospital Zürich, Zürich, CH-8091, Switzerland
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41
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Azam S, Haque ME, Balakrishnan R, Kim IS, Choi DK. The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration. Front Cell Dev Biol 2021; 9:683459. [PMID: 34485280 PMCID: PMC8414981 DOI: 10.3389/fcell.2021.683459] [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: 03/21/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
Ageing is an inevitable event in the lifecycle of all organisms, characterized by progressive physiological deterioration and increased vulnerability to death. Ageing has also been described as the primary risk factor of most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and frontotemporal lobar dementia (FTD). These neurodegenerative diseases occur more prevalently in the aged populations. Few effective treatments have been identified to treat these epidemic neurological crises. Neurodegenerative diseases are associated with enormous socioeconomic and personal costs. Here, the pathogenesis of AD, PD, and other neurodegenerative diseases has been presented, including a summary of their known associations with the biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communications. Understanding the central biological mechanisms that underlie ageing is important for identifying novel therapeutic targets for neurodegenerative diseases. Potential therapeutic strategies, including the use of NAD+ precursors, mitophagy inducers, and inhibitors of cellular senescence, has also been discussed.
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Affiliation(s)
- Shofiul Azam
- Department of Applied Life Sciences, Graduate School, BK21 Program, Konkuk University, Chungju-si, South Korea
| | - Md. Ezazul Haque
- Department of Applied Life Sciences, Graduate School, BK21 Program, Konkuk University, Chungju-si, South Korea
| | - Rengasamy Balakrishnan
- Department of Applied Life Sciences, Graduate School, BK21 Program, Konkuk University, Chungju-si, South Korea
| | - In-Su Kim
- Department of Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju-si, South Korea
| | - Dong-Kug Choi
- Department of Applied Life Sciences, Graduate School, BK21 Program, Konkuk University, Chungju-si, South Korea
- Department of Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju-si, South Korea
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42
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Ko DWK. Transcutaneous vagus nerve stimulation (tVNS) as a potential therapeutic application for neurodegenerative disorders - A focus on dysautonomia in Parkinson's disease. Auton Neurosci 2021; 235:102858. [PMID: 34365230 DOI: 10.1016/j.autneu.2021.102858] [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: 05/29/2021] [Revised: 07/12/2021] [Accepted: 07/20/2021] [Indexed: 11/29/2022]
Abstract
The understandings of pathogenic processes in major neurodegenerative diseases has significantly advanced in recent years, with evidence showing pathological spread of intraneuronal proteinaceous inclusions as a fundamental factor. In Parkinson's disease (PD), the culprit protein has been identified as α-synuclein as the main component for mediating progressive neurodegeneration. With severe pathology evident in the autonomic nervous system prior to clinical manifestations of PD, pathogenic spread can occur from the peripheral nervous system through key nuclei, such as the anterior olfactory nucleus and dorsal motor nucleus of the glossopharyngeal and vagal nerves, gradually reaching the brainstem, midbrain and cerebral cortex. With this understanding and the proposed involvement of the vagus nerve in disease progression in PD, notably occurring prior to characterized clinical motor features, it raises intriguing questions as to whether vagal nerve pathology can be accurately detected, and importantly used as a reliable marker for determining early neurodegeneration. Along with this is the potential use of vagus nerve neuromodulation for treatment of early disease symptoms like dysautonomia, for modulating sympatho-vagal imbalances and easing severe comorbidities of the disease. In this article, we take a closer look at the pathogenic transmission processes in neurodegenerative disorders that impact the vagus nerve, and how vagus nerve neuromodulation can be potentially applied as a therapeutic approach for major neurodegenerative disorders.
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Affiliation(s)
- Daniel W K Ko
- Neuropix Company Ltd, Core F, Cyberport 3, 100 Cyberport Road, Hong Kong Special Administrative Region.
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43
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King-Robson J, Wilson H, Politis M. Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer's Disease and Mild Cognitive Impairment. J Alzheimers Dis 2021; 82:541-560. [PMID: 34057079 DOI: 10.3233/jad-201457] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The roles of amyloid-β and tau in the degenerative process of Alzheimer's disease (AD) remain uncertain. [18F]AV-45 and [18F]AV-1451 PET quantify amyloid-β and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. OBJECTIVE Examine the impact of amyloid-β and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. METHODS Combined [18F]AV-45 and [18F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. RESULTS Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p < 0.05). Hippocampal strength inversely correlated with [18F]AV-1451 SUVr in MCI (r = -0.55, p = 0.049) and AD (r = -0.57, p = 0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [18F]AV-45 SUVr in those same regions in MCI (r = -0.33, p = 0.003) and AD (r = -0.31, p = 0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r = -0.60, p = 0.035) and left hippocampus in AD (r = 0.69, p = 0.024). Clinical Dementia Rating Scale scores correlated with [18F]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r = 0.65, p = 0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r = 0.062, p = 0.009) parahippocampal gyrus in AD. CONCLUSION Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-β in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology.
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Affiliation(s)
- Josh King-Robson
- Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK
| | - Heather Wilson
- Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.,Neurodegeneration Imaging Group, University of Exeter Medical School, London, UK
| | - Marios Politis
- Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.,Neurodegeneration Imaging Group, University of Exeter Medical School, London, UK
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44
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Cata JP, Uhelski ML, Gorur A, Dougherty PM. Nociception and Pain: New Roles for Exosomes. Neuroscientist 2021; 28:349-363. [PMID: 34166130 DOI: 10.1177/10738584211027105] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The interchange of information from one cell to another relies on the release of hundreds of different molecules including small peptides, amino acids, nucleotides, RNA, steroids, retinoids, or fatty acid metabolites. Many of them are released to the extracellular matrix as free molecules and others can be part of the cargo of cellular vesicles. Small extracellular vesicles (30-150 nm), also known as exosomes, are a known mechanism of cell-to-cell communication in the nervous system. Exosomes participate in the pathogenesis of several neurological conditions including Alzheimer's and Parkinson's disease. However, exciting emerging evidence demonstrates that exosomes also regulate mechanisms of the sensory process including nociception. The goal of this review is to summarize the literature on exosome biogenesis, methods of small vesicle isolation and purification, and their role in nociception. We also provide insights on the potential applications of exosomes as pain biomarkers or as novel therapeutics.
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Affiliation(s)
- Juan P Cata
- Department of Anesthesiology and Perioperative Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA.,Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA
| | - Megan L Uhelski
- Department of Pain Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA
| | - Aysegul Gorur
- Department of Anesthesiology and Perioperative Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA.,Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA
| | - Patrick M Dougherty
- Department of Pain Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA
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45
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Kara E, Crimi A, Wiedmer A, Emmenegger M, Manzoni C, Bandres-Ciga S, D'Sa K, Reynolds RH, Botía JA, Losa M, Lysenko V, Carta M, Heinzer D, Avar M, Chincisan A, Blauwendraat C, García-Ruiz S, Pease D, Mottier L, Carrella A, Beck-Schneider D, Magalhães AD, Aemisegger C, Theocharides APA, Fan Z, Marks JD, Hopp SC, Abramov AY, Lewis PA, Ryten M, Hardy J, Hyman BT, Aguzzi A. An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein. Cell Rep 2021; 35:109189. [PMID: 34107263 PMCID: PMC8207177 DOI: 10.1016/j.celrep.2021.109189] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/08/2021] [Accepted: 05/07/2021] [Indexed: 12/13/2022] Open
Abstract
Neuropathological and experimental evidence suggests that the cell-to-cell transfer of α-synuclein has an important role in the pathogenesis of Parkinson's disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook a small interfering RNA (siRNA), genome-wide screen to identify genes regulating the cell-to-cell transfer of α-synuclein. A genetically encoded reporter, GFP-2A-αSynuclein-RFP, suitable for separating donor and recipient cells, was transiently transfected into HEK cells stably overexpressing α-synuclein. We find that 38 genes regulate the transfer of α-synuclein-RFP, one of which is ITGA8, a candidate gene identified through a recent PD genome-wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) show that those hits cluster in networks that include known PD genes more frequently than expected by random chance. The findings expand our understanding of the mechanism of α-synuclein spread.
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Affiliation(s)
- Eleanna Kara
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland; Department of Neurodegenerative disease, University College London, London WC1N 3BG, UK
| | - Alessandro Crimi
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Anne Wiedmer
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Marc Emmenegger
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Claudia Manzoni
- Department of Pharmacology, University College London School of Pharmacy, London WC1N 1AX, UK; School of Pharmacy, University of Reading, Reading RG6 6AP, UK
| | - Sara Bandres-Ciga
- Laboratory of Neurogenetics, National Institutes of Health, Bethesda, MD 20814, USA
| | - Karishma D'Sa
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Regina H Reynolds
- Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
| | - Juan A Botía
- Department of Neurodegenerative disease, University College London, London WC1N 3BG, UK; Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia 30100, Spain
| | - Marco Losa
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Veronika Lysenko
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich 8091, Switzerland
| | - Manfredi Carta
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Daniel Heinzer
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Merve Avar
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Andra Chincisan
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | | | - Sonia García-Ruiz
- Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
| | - Daniel Pease
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Lorene Mottier
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Alessandra Carrella
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Dezirae Beck-Schneider
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Andreia D Magalhães
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland
| | - Caroline Aemisegger
- Center for Microscopy and Image Analysis, University of Zurich, Zurich 8057, Switzerland
| | - Alexandre P A Theocharides
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich 8091, Switzerland
| | - Zhanyun Fan
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Jordan D Marks
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Sarah C Hopp
- Department of Pharmacology, UT Health San Antonio, San Antonio, TX 78229, USA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Andrey Y Abramov
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
| | - Patrick A Lewis
- Department of Neurodegenerative disease, University College London, London WC1N 3BG, UK; School of Pharmacy, University of Reading, Reading RG6 6AP, UK; Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK
| | - Mina Ryten
- Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
| | - John Hardy
- Department of Neurodegenerative disease, University College London, London WC1N 3BG, UK; UK Dementia Research Institute, University College London, London WC1N 3BG, UK; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK; Institute for Advanced Study, the Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Bradley T Hyman
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Adriano Aguzzi
- Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland.
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Navalkar A, Pandey S, Singh N, Patel K, Datta D, Mohanty B, Jadhav S, Chaudhari P, Maji SK. Direct evidence of cellular transformation by prion-like p53 amyloid infection. J Cell Sci 2021; 134:269011. [PMID: 34085695 DOI: 10.1242/jcs.258316] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/21/2021] [Indexed: 11/20/2022] Open
Abstract
Tumor suppressor p53 mutations are associated with more than 50% of cancers. Aggregation and amyloid formation of p53 is also implicated in cancer pathogenesis, but direct evidence for aggregated p53 amyloids acting as an oncogene is lacking. Here, we conclusively demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to non-cancerous cells. p53 amyloid aggregates were transferred through cell generations, contributing to enhanced survival, apoptotic resistance with increased proliferation and migration. The tumorigenic potential of p53 amyloid-transformed cells was further confirmed in mouse xenografts, wherein the tumors showed p53 amyloids. p53 disaggregation rescued the cellular transformation and inhibited tumor development in mice. We propose that wild-type p53 amyloid formation contributes to tumorigenesis and can be a potential target for therapeutic intervention. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Ambuja Navalkar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India400076
| | - Satyaprakash Pandey
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India400076
| | - Namrata Singh
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India400076
| | - Komal Patel
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India400076
| | - Debalina Datta
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India400076
| | - Bhabani Mohanty
- Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, India410210
| | | | - Pradip Chaudhari
- Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, India410210.,Department of Life Sciences, Homi Bhabha National Institute, Anushaktinagar, Mumbai, India400094
| | - Samir K Maji
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India400076
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Ding X, Xiang Z, Qin C, Chen Y, Tian H, Meng L, Xia D, Liu H, Song J, Fu J, Ma M, Wang X. Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice. Acta Neuropathol Commun 2021; 9:15. [PMID: 33461623 PMCID: PMC7814549 DOI: 10.1186/s40478-020-01112-3] [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: 10/09/2020] [Accepted: 12/23/2020] [Indexed: 12/18/2022] Open
Abstract
Transactive response DNA-binding protein 43 kDa (TDP-43) has been identified as the major component of ubiquitinated inclusions found in patients with sporadic amyotrophic lateral sclerosis (ALS). Increasing evidence suggests prion-like transmission of TDP-43 aggregates via neuroanatomic connection in vitro and pyramidal tract in vivo. However, it is still unknown whether the spreading of pathological TDP-43 sequentially via pyramidal tract can initiate ALS-like pathology and phenotypes. In this study, we reported that injection of TDP-43 preformed fibrils (PFFs) into the primary motor cortex (M1) of Thy1-e (IRES-TARDBP) 1 mice induced the spreading of pathological TDP-43 along pyramidal tract axons anterogradely. Moreover, TDP-43 PFFs-injected Thy1-e (IRES-TARDBP) 1 mice displayed ALS-like neuropathological features and symptoms, including motor dysfunctions and electrophysiological abnormalities. These findings provide direct evidence that transmission of pathological TDP-43 along pyramidal tract induces ALS-like phenotypes, which further suggest the potential mechanism for TDP-43 proteinopathy.
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Billant O, Friocourt G, Roux P, Voisset C. p53, A Victim of the Prion Fashion. Cancers (Basel) 2021; 13:E269. [PMID: 33450819 PMCID: PMC7828285 DOI: 10.3390/cancers13020269] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 12/17/2022] Open
Abstract
Identified in the late 1970s as an oncogene, a driving force leading to tumor development, p53 turned out to be a key tumor suppressor gene. Now p53 is considered a master gene regulating the transcription of over 3000 target genes and controlling a remarkable number of cellular functions. The elevated prevalence of p53 mutations in human cancers has led to a recurring questioning about the roles of mutant p53 proteins and their functional consequences. Both mutants and isoforms of p53 have been attributed dominant-negative and gain of function properties among which is the ability to form amyloid aggregates and behave in a prion-like manner. This report challenges the ongoing "prion p53" hypothesis by reviewing evidence of p53 behavior in light of our current knowledge regarding amyloid proteins, prionoids and prions.
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Affiliation(s)
| | - Gaëlle Friocourt
- Inserm, Université de Bretagne Occidentale, EFS, UMR 1078, GGB, F-29200 Brest, France;
| | - Pierre Roux
- CRBM, CNRS, UMR5234, 34293 Montpellier, France;
| | - Cécile Voisset
- Inserm, Université de Bretagne Occidentale, EFS, UMR 1078, GGB, F-29200 Brest, France;
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49
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Louka A, Zacco E, Temussi PA, Tartaglia GG, Pastore A. RNA as the stone guest of protein aggregation. Nucleic Acids Res 2020; 48:11880-11889. [PMID: 33068411 PMCID: PMC7708036 DOI: 10.1093/nar/gkaa822] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/12/2020] [Accepted: 10/14/2020] [Indexed: 12/13/2022] Open
Abstract
The study of prions as infectious aggregates dates several decades. From its original formulation, the definition of a prion has progressively changed to the point that many aggregation-prone proteins are now considered bona fide prions. RNA molecules, not included in the original 'protein-only hypothesis', are also being recognized as important factors contributing to the 'prion behaviour', that implies the transmissibility of an aberrant fold. In particular, an association has recently emerged between aggregation and the assembly of prion-like proteins in RNA-rich complexes, associated with both physiological and pathological events. Here, we discuss the historical rising of the concept of prion-like domains, their relation to RNA and their role in protein aggregation. As a paradigmatic example, we present the case study of TDP-43, an RNA-binding prion-like protein associated with amyotrophic lateral sclerosis. Through this example, we demonstrate how the current definition of prions has incorporated quite different concepts making the meaning of the term richer and more stimulating. An important message that emerges from our analysis is the dual role of RNA in protein aggregation, making RNA, that has been considered for many years a 'silent presence' or the 'stone guest' of protein aggregation, an important component of the process.
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Affiliation(s)
- Alexandra Louka
- UK Dementia Research Institute at the Maurice Wohl Institute of King's College London, London SE5 9RT, UK
| | - Elsa Zacco
- Center for Human Technologies, Central RNA laboratory, Istituto Italiano di Tecnologia, Genova 16152, Italy
| | - Piero Andrea Temussi
- UK Dementia Research Institute at the Maurice Wohl Institute of King's College London, London SE5 9RT, UK
- University “Federico II’’ Napoli, via Cynthia, Napoli 80100, Italy
| | - Gian Gaetano Tartaglia
- Center for Human Technologies, Central RNA laboratory, Istituto Italiano di Tecnologia, Genova 16152, Italy
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain and ICREA, 23 Passeig Lluıs Companys, Barcelona 08010, Spain
- Charles Darwin department of Biology and Biotechnology, Sapienza University of Rome, Piazzale A. Moro 5, Rome 00185, Italy
| | - Annalisa Pastore
- UK Dementia Research Institute at the Maurice Wohl Institute of King's College London, London SE5 9RT, UK
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Dominguez-Meijide A, Vasili E, Outeiro TF. Pharmacological Modulators of Tau Aggregation and Spreading. Brain Sci 2020; 10:E858. [PMID: 33203009 PMCID: PMC7696562 DOI: 10.3390/brainsci10110858] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/09/2020] [Accepted: 11/11/2020] [Indexed: 12/25/2022] Open
Abstract
Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.
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Affiliation(s)
- Antonio Dominguez-Meijide
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073 Goettingen, Germany; (A.D.-M.); (E.V.)
- Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Eftychia Vasili
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073 Goettingen, Germany; (A.D.-M.); (E.V.)
| | - Tiago Fleming Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073 Goettingen, Germany; (A.D.-M.); (E.V.)
- Max Planck Institute for Experimental Medicine, 37075 Goettingen, Germany
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK
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