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Zhao R. Can exercise benefits be harnessed with drugs? A new way to combat neurodegenerative diseases by boosting neurogenesis. Transl Neurodegener 2024; 13:36. [PMID: 39049102 PMCID: PMC11271207 DOI: 10.1186/s40035-024-00428-7] [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: 02/02/2024] [Accepted: 07/01/2024] [Indexed: 07/27/2024] Open
Abstract
Adult hippocampal neurogenesis (AHN) is affected by multiple factors, such as enriched environment, exercise, ageing, and neurodegenerative disorders. Neurodegenerative disorders can impair AHN, leading to progressive neuronal loss and cognitive decline. Compelling evidence suggests that individuals engaged in regular exercise exhibit higher production of proteins that are essential for AHN and memory. Interestingly, specific molecules that mediate the effects of exercise have shown effectiveness in promoting AHN and cognition in different transgenic animal models. Despite these advancements, the precise mechanisms by which exercise mimetics induce AHN remain partially understood. Recently, some novel exercise molecules have been tested and the underlying mechanisms have been proposed, involving intercommunications between multiple organs such as muscle-brain crosstalk, liver-brain crosstalk, and gut-brain crosstalk. In this review, we will discuss the current evidence regarding the effects and potential mechanisms of exercise mimetics on AHN and cognition in various neurological disorders. Opportunities, challenges, and future directions in this research field are also discussed.
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Affiliation(s)
- Renqing Zhao
- College of Physical Education, Yangzhou University, 88 South Daxue Road, Yangzhou, 225009, China.
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2
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Oz T, Kaushik A, Kujawska M. Neural stem cells for Parkinson's disease management: Challenges, nanobased support, and prospects. World J Stem Cells 2023; 15:687-700. [PMID: 37545757 PMCID: PMC10401423 DOI: 10.4252/wjsc.v15.i7.687] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/27/2023] [Accepted: 05/16/2023] [Indexed: 07/25/2023] Open
Abstract
Parkinson's disease (PD), characterized by loss of nigrostriatal dopaminergic neurons, is one of the most predominant neurodegenerative diseases affecting the elderly population worldwide. The concept of stem cell therapy in managing neurodegenerative diseases has evolved over the years and has recently rapidly progressed. Neural stem cells (NSCs) have a few key features, including self-renewal, proliferation, and multipotency, which make them a promising agent targeting neurodegeneration. It is generally agreed that challenges for NSC-based therapy are present at every stage of the transplantation process, including preoperative cell preparation and quality control, perioperative procedures, and postoperative graft preservation, adherence, and overall therapy success. In this review, we provided a comprehensive, careful, and critical discussion of experimental and clinical data alongside the pros and cons of NSC-based therapy in PD. Given the state-of-the-art accomplishments of stem cell therapy, gene therapy, and nanotechnology, we shed light on the perspective of complementing the advantages of each process by developing nano-stem cell therapy, which is currently a research hotspot. Although various obstacles and challenges remain, nano-stem cell therapy holds promise to cure PD, however, continuous improvement and development from the stage of laboratory experiments to the clinical application are necessary.
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Affiliation(s)
- Tuba Oz
- Department of Toxicology, Poznan University of Medical Sciences, Poznan 60-631, Poland
| | - Ajeet Kaushik
- NanoBioTech Laboratory, Health System Engineering, Department of Environmental Engineering, Florida Polytechnic University, Lakeland, FL 33805, United States
- School of Engineering, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Małgorzata Kujawska
- Department of Toxicology, Poznan University of Medical Sciences, Poznan 60-631, Poland.
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Yin B, Li H, Zhao P, Zhao Y, Zheng R, Feng P, Xu C, Li E, Li L. GM1 Reduced the Symptoms of Autism Spectrum Disorder by Suppressing α-Syn Through Activating Autophagy. J Mol Neurosci 2023; 73:287-296. [PMID: 37084025 DOI: 10.1007/s12031-023-02110-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 02/24/2023] [Indexed: 04/22/2023]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that cannot be cured. The ASD rat model was developed in this study to demonstrate the role and mechanism of ganglioside GM1 (GM1). Rats were given valproic acid (VPA) to create the ASD rat model. The rats' behaviors were assessed using the Y-maze test, open-field test, three-chamber social interaction test, and Morris water maze test. Relative levels of glutathione (GSH), malondialdehyde (MDA), catalase (CAT), reactive oxygen species (ROS), and superoxide dismutase (SOD) were quantitated using relative kits. Nissl, TUNEL, immunofluorescent, and immunohistochemistry staining techniques were used. GM1 treatment improved the ASD model rats' behavior disorders, including locomotor activity and exploratory behavior, social interaction, learning and memory capacity, and repetitive behavior. Following GM1 injection, striatal neurons grew and apoptosis decreased. GM1 reduced the excessively elevated α-Syn in ASD by encouraging autophagy. The behavior disorder of ASD model rats was exacerbated by autophagy inhibition, which also increased α-Syn levels. By increasing autophagy, GM1 reduced α-Syn levels and, ultimately, improved behavioral abnormalities in ASD model rats.
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Affiliation(s)
- Baoqi Yin
- Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, No.3 Rehabilitation Street, Zhengzhou, 450052, People's Republic of China
| | - Honglei Li
- Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, No.3 Rehabilitation Street, Zhengzhou, 450052, People's Republic of China
| | - Pengju Zhao
- Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, No.3 Rehabilitation Street, Zhengzhou, 450052, People's Republic of China
| | - Yonghong Zhao
- Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, No.3 Rehabilitation Street, Zhengzhou, 450052, People's Republic of China
| | - Ruijuan Zheng
- Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, No.3 Rehabilitation Street, Zhengzhou, 450052, People's Republic of China
| | - Pengya Feng
- Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, No.3 Rehabilitation Street, Zhengzhou, 450052, People's Republic of China
| | - Cuixiang Xu
- Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, No.3 Rehabilitation Street, Zhengzhou, 450052, People's Republic of China
| | - Enyao Li
- Department of Children Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, No.3 Rehabilitation Street, Zhengzhou, 450052, People's Republic of China.
| | - Liguo Li
- Department of Rehabilitation Medicine, Zhengzhou Health Vocational College, No. 69 Jingxiang Road, Zhengzhou, 450000, People's Republic of China.
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Martin-Lopez E, Vidyadhara DJ, Liberia T, Meller SJ, Harmon LE, Hsu RM, Spence N, Brennan B, Han K, Yücel B, Chandra SS, Greer CA. α-Synuclein Pathology and Reduced Neurogenesis in the Olfactory System Affect Olfaction in a Mouse Model of Parkinson's Disease. J Neurosci 2023; 43:1051-1071. [PMID: 36596700 PMCID: PMC9908323 DOI: 10.1523/jneurosci.1526-22.2022] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 12/09/2022] [Accepted: 12/15/2022] [Indexed: 01/05/2023] Open
Abstract
Parkinson's disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathologic changes in the olfactory pathway of transgenic (Tg) mice of both sexes expressing the human A30P mutant α-synuclein (α-syn; α-syn-Tg mice) at 6-7 and 12-14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons (PNs) of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at six to seven months and OB periglomerular cells at 12-14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endocytic and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12-14 months. Our data suggest that (1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD; (2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology; (3) α-syn pathology is restricted to projection neurons in the olfactory pathway; (4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and (5) synaptic endocytosis and exocytosis defects in the OB may further explain olfactory deficits.SIGNIFICANCE STATEMENT Olfactory dysfunction is a characteristic symptom of Parkinson's disease (PD). Using the human A30P mutant α-synuclein (α-syn)-expressing mouse model, we demonstrated the appearance of olfactory deficits at late stages of the disease, which was accompanied by the accumulation of α-syn pathology in projection neurons (PNs) of the olfactory system. This dysfunction included a reduction in olfactory bulb (OB) neurogenesis as well as changes in synaptic vesicular transport affecting synaptic function, both of which are likely contributing to olfactory behavioral deficits.
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Affiliation(s)
- Eduardo Martin-Lopez
- Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - D J Vidyadhara
- Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Teresa Liberia
- Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Sarah J Meller
- Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Leah E Harmon
- Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Ryan M Hsu
- Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Natalie Spence
- Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Bowen Brennan
- Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Kimberly Han
- Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Betül Yücel
- Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Sreeganga S Chandra
- Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Charles A Greer
- Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510
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The Dialogue Between Neuroinflammation and Adult Neurogenesis: Mechanisms Involved and Alterations in Neurological Diseases. Mol Neurobiol 2023; 60:923-959. [PMID: 36383328 DOI: 10.1007/s12035-022-03102-z] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 10/23/2022] [Indexed: 11/18/2022]
Abstract
Adult neurogenesis occurs mainly in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles. Evidence supports the critical role of adult neurogenesis in various conditions, including cognitive dysfunction, Alzheimer's disease (AD), and Parkinson's disease (PD). Several factors can alter adult neurogenesis, including genetic, epigenetic, age, physical activity, diet, sleep status, sex hormones, and central nervous system (CNS) disorders, exerting either pro-neurogenic or anti-neurogenic effects. Compelling evidence suggests that any insult or injury to the CNS, such as traumatic brain injury (TBI), infectious diseases, or neurodegenerative disorders, can provoke an inflammatory response in the CNS. This inflammation could either promote or inhibit neurogenesis, depending on various factors, such as chronicity and severity of the inflammation and underlying neurological disorders. Notably, neuroinflammation, driven by different immune components such as activated glia, cytokines, chemokines, and reactive oxygen species, can regulate every step of adult neurogenesis, including cell proliferation, differentiation, migration, survival of newborn neurons, maturation, synaptogenesis, and neuritogenesis. Therefore, this review aims to present recent findings regarding the effects of various components of the immune system on adult neurogenesis and to provide a better understanding of the role of neuroinflammation and neurogenesis in the context of neurological disorders, including AD, PD, ischemic stroke (IS), seizure/epilepsy, TBI, sleep deprivation, cognitive impairment, and anxiety- and depressive-like behaviors. For each disorder, some of the most recent therapeutic candidates, such as curcumin, ginseng, astragaloside, boswellic acids, andrographolide, caffeine, royal jelly, estrogen, metformin, and minocycline, have been discussed based on the available preclinical and clinical evidence.
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Lee JE, Shin YJ, Kim YS, Kim HN, Kim DY, Chung SJ, Yoo HS, Shin JY, Lee PH. Uric Acid Enhances Neurogenesis in a Parkinsonian Model by Remodeling Mitochondria. Front Aging Neurosci 2022; 14:851711. [PMID: 35721028 PMCID: PMC9201452 DOI: 10.3389/fnagi.2022.851711] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 05/06/2022] [Indexed: 12/02/2022] Open
Abstract
Background Adult neurogenesis is the process of generating new neurons to enter neural circuits and differentiate into functional neurons. However, it is significantly reduced in Parkinson’s disease (PD). Uric acid (UA), a natural antioxidant, has neuroprotective properties in patients with PD. This study aimed to investigate whether UA would enhance neurogenesis in PD. Methods We evaluated whether elevating serum UA levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model would restore neurogenesis in the subventricular zone (SVZ). For a cellular model, we primary cultured neural precursor cells (NPCs) from post-natal day 1 rat and evaluated whether UA treatment promoted cell proliferation against 1-methyl-4-phenylpyridinium (MPP+). Results Uric acid enhanced neurogenesis in both in vivo and in vitro parkinsonian model. UA-elevating therapy significantly increased the number of bromodeoxyuridine (BrdU)-positive cells in the SVZ of PD animals as compared to PD mice with normal UA levels. In a cellular model, UA treatment increased the expression of Ki-67. In the process of modulating neurogenesis, UA elevation up-regulated the expression of mitochondrial fusion markers. Conclusion In MPTP-induced parkinsonian model, UA probably enhanced neurogenesis via regulating mitochondrial dynamics, promoting fusion machinery, and inhibiting fission process.
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Affiliation(s)
- Ji Eun Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Yu Jin Shin
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Yi Seul Kim
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Ha Na Kim
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Yeol Kim
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Seok Jong Chung
- Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin, South Korea
| | - Han Soo Yoo
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Jin Young Shin
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Yonsei University, Seoul, South Korea
| | - Phil Hyu Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Yonsei University, Seoul, South Korea
- *Correspondence: Phil Hyu Lee,
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7
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Culig L, Chu X, Bohr VA. Neurogenesis in aging and age-related neurodegenerative diseases. Ageing Res Rev 2022; 78:101636. [PMID: 35490966 PMCID: PMC9168971 DOI: 10.1016/j.arr.2022.101636] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 04/14/2022] [Accepted: 04/25/2022] [Indexed: 12/11/2022]
Abstract
Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aβ, α-synuclein, …). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.
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Affiliation(s)
- Luka Culig
- Section on DNA Repair, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Xixia Chu
- Section on DNA Repair, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Vilhelm A Bohr
- Section on DNA Repair, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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Novel Approaches Used to Examine and Control Neurogenesis in Parkinson's Disease. Int J Mol Sci 2021; 22:ijms22179608. [PMID: 34502516 PMCID: PMC8431772 DOI: 10.3390/ijms22179608] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/16/2022] Open
Abstract
Neurogenesis is a key mechanism of brain development and plasticity, which is impaired in chronic neurodegeneration, including Parkinson’s disease. The accumulation of aberrant α-synuclein is one of the features of PD. Being secreted, this protein produces a prominent neurotoxic effect, alters synaptic plasticity, deregulates intercellular communication, and supports the development of neuroinflammation, thereby providing propagation of pathological events leading to the establishment of a PD-specific phenotype. Multidirectional and ambiguous effects of α-synuclein on adult neurogenesis suggest that impaired neurogenesis should be considered as a target for the prevention of cell loss and restoration of neurological functions. Thus, stimulation of endogenous neurogenesis or cell-replacement therapy with stem cell-derived differentiated neurons raises new hopes for the development of effective and safe technologies for treating PD neurodegeneration. Given the rapid development of optogenetics, it is not surprising that this method has already been repeatedly tested in manipulating neurogenesis in vivo and in vitro via targeting stem or progenitor cells. However, niche astrocytes could also serve as promising candidates for controlling neuronal differentiation and improving the functional integration of newly formed neurons within the brain tissue. In this review, we mainly focus on current approaches to assess neurogenesis and prospects in the application of optogenetic protocols to restore the neurogenesis in Parkinson’s disease.
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Kamte YS, Chandwani MN, Michaels AC, O’Donnell LA. Neural Stem Cells: What Happens When They Go Viral? Viruses 2021; 13:v13081468. [PMID: 34452333 PMCID: PMC8402908 DOI: 10.3390/v13081468] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/22/2021] [Accepted: 06/28/2021] [Indexed: 12/25/2022] Open
Abstract
Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.
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Bender H, Fietz SA, Richter F, Stanojlovic M. Alpha-Synuclein Pathology Coincides With Increased Number of Early Stage Neural Progenitors in the Adult Hippocampus. Front Cell Dev Biol 2021; 9:691560. [PMID: 34307368 PMCID: PMC8293917 DOI: 10.3389/fcell.2021.691560] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 06/15/2021] [Indexed: 12/19/2022] Open
Abstract
Alpha-synuclein pathology driven impairment in adult neurogenesis was proposed as a potential cause of, or at least contributor to, memory impairment observed in both patients and animal models of Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Mice overexpressing wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, line 61) uniquely replicate early cognitive deficits together with multiple other characteristic motor and non-motor symptoms, alpha-synuclein pathology and dopamine loss. Here we report overt intracellular accumulation of phosphorylated alpha-synuclein in the hippocampus of these transgenic mice. To test whether this alters adult neurogenesis and total number of mature neurons, we employed immunohistochemistry and an unbiased stereology approach to quantify the distinct neural progenitor cells and neurons in the hippocampal granule cell layer and subgranular zone of 6 (prodromal stage) and 16-month (dopamine loss) old Thy1-aSyn mice. Surprisingly, we observed an increase in the number of early stage, i.e., Pax6 expressing, progenitors whereas the numbers of late stage, i.e., Tbr2 expressing, progenitors and neurons were not altered. Astroglia marker was increased in the hippocampus of transgenic mice, but this was not specific to the regions where adult neurogenesis takes place, arguing against a commitment of additional early stage progenitors to the astroglia lineage. Together, this uncovers a novel aspect of alpha-synuclein pathology in adult neurogenesis. Studying its mechanisms in Thy1-aSyn mice could lead to discovery of effective therapeutic interventions for cognitive dysfunction in PD and DLB.
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Affiliation(s)
- Hannah Bender
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany
| | - Simone A Fietz
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany
| | - Franziska Richter
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hanover, Germany.,Center for Systems Neuroscience, Hanover, Germany
| | - Milos Stanojlovic
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hanover, Germany
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Bang Y, Lim J, Choi HJ. Recent advances in the pathology of prodromal non-motor symptoms olfactory deficit and depression in Parkinson's disease: clues to early diagnosis and effective treatment. Arch Pharm Res 2021; 44:588-604. [PMID: 34145553 PMCID: PMC8254697 DOI: 10.1007/s12272-021-01337-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/01/2021] [Indexed: 12/14/2022]
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by movement dysfunction due to selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. Non-motor symptoms of PD (e.g., sensory dysfunction, sleep disturbance, constipation, neuropsychiatric symptoms) precede motor symptoms, appear at all stages, and impact the quality of life, but they frequently go unrecognized and remain untreated. Even when identified, traditional dopamine replacement therapies have little effect. We discuss here the pathology of two PD-associated non-motor symptoms: olfactory dysfunction and depression. Olfactory dysfunction is one of the earliest non-motor symptoms in PD and predates the onset of motor symptoms. It is accompanied by early deposition of Lewy pathology and neurotransmitter alterations. Because of the correlation between olfactory dysfunction and an increased risk of progression to PD, olfactory testing can potentially be a specific diagnostic marker of PD in the prodromal stage. Depression is a prevalent PD-associated symptom and is often associated with reduced quality of life. Although the pathophysiology of depression in PD is unclear, studies suggest a causal relationship with abnormal neurotransmission and abnormal adult neurogenesis. Here, we summarize recent progress in the pathology of the non-motor symptoms of PD, aiming to provide better guidance for its effective management.
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Affiliation(s)
- Yeojin Bang
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do, 11160, Republic of Korea
| | - Juhee Lim
- College of Pharmacy, Woosuk University, Wanju, Jeollabuk-do, 55338, Republic of Korea
| | - Hyun Jin Choi
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon, Gyeonggi-do, 11160, Republic of Korea.
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Sherstnev VV, Solov’eva OA, Gruden’ MA, Ratmirov AM, Konovalova EV. Hippocampal Neurogenesis, Dopaminergic Neurons of the Substantia Nigra, and Behavior after Intranasal Administration of Native α-Synuclein Protein to Ageing Mice. NEUROCHEM J+ 2021. [DOI: 10.1134/s181971242101013x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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13
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Karlsson L, González-Alvarado MN, Motalleb R, Wang Y, Wang Y, Börjesson M, Zhu C, Kuhn HG. Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Contribute to Exercise-Induced Neurogenesis. Mol Neurobiol 2021; 58:1465-1481. [PMID: 33200398 PMCID: PMC7932943 DOI: 10.1007/s12035-020-02189-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 10/27/2020] [Indexed: 01/04/2023]
Abstract
Physical exercise can improve age-dependent decline in cognition, which in rodent is partly mediated by restoration of an age-dependent decline in neurogenesis. Exercise-inducible myokines in the circulation present a link in muscle-brain crosstalk. The transcription factor PGC-1α regulates the release of such myokines with neurotrophic properties into the circulation. We study how chronic muscular overexpression of PGC-1α could contribute to exercise-induced effects on hippocampal neurogenesis and if this effect could be enhanced in a running wheel paradigm. We used 3- and 11-month-old transgenic mice with overexpression of PGC-1α under the control of muscle creatinine kinase promoter (MCK-PGC-1α), which have a constitutively developed endurance muscle phenotype. Wild-type and MCK-PGC-1α mice were single housed with free access to running wheels. Four weeks of running in female animals increased the levels of newborn cells, immature neurons, and, for young animals, new mature neurons, compared to sedentary controls. However, no difference in these parameters was observed between wild-type and transgenic mice under sedentary or running conditions. Multiplex analysis of serum cytokines, chemokines, and myokines suggested several differences in serum protein concentrations between genotypes with musclin found to be significantly upregulated 4-fold in male MCK-PGC-1α animals. We conclude that constitutive muscular overexpression of PGC-1α, despite systemic changes and difference in serum composition, does not translate into exercise-induced effects on hippocampal neurogenesis, independent of the age of the animal. This suggests that chronic activation of PGC-1α in skeletal muscle is by itself not sufficient to mimic exercise-induced effects or to prevent decline of neurogenesis in aging.
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Affiliation(s)
- Lars Karlsson
- Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
- The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Region of Western Sweden, Gothenburg, Sweden.
| | - María Nazareth González-Alvarado
- Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Reza Motalleb
- Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Yafeng Wang
- Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Pediatrics, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yong Wang
- Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mats Börjesson
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy and Center for Health and Performance, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska University Hospital/Östra, Region of Western Sweden, Gothenburg, Sweden
| | - Changlian Zhu
- Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hans-Georg Kuhn
- Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
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14
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Brown SJ, Boussaad I, Jarazo J, Fitzgerald JC, Antony P, Keatinge M, Blechman J, Schwamborn JC, Krüger R, Placzek M, Bandmann O. PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons. Sci Rep 2021; 11:6617. [PMID: 33758225 PMCID: PMC7988014 DOI: 10.1038/s41598-021-84278-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/09/2021] [Indexed: 12/14/2022] Open
Abstract
Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson's disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons in two complementary model systems. Zebrafish are a widely-used model to study neurogenesis in development and through adulthood. Using EdU analyses and lineage-tracing studies, we first demonstrate that a subset of ascending DA neurons and adjacent local-projecting DA neurons are each generated into adulthood in wild type zebrafish at a rate that decreases with age. Pink1-deficiency impedes DA neurogenesis in these populations, most significantly in early adult life. Pink1 already exerts an early effect on Th1+ progenitor cells rather than on differentiated DA neurons only. In addition, we investigate the effect of PINK1 deficiency in a human isogenic organoid model. Global neuronal differentiation in PINK1-deficient organoids and isogenic controls is similar, but PINK1-deficient organoids display impeded DA neurogenesis. The observation of impaired adult dopaminergic neurogenesis in Pink1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in human PD patients with biallelic PINK1 mutations.
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Affiliation(s)
- Sarah J Brown
- Bateson Centre, University of Sheffield, Sheffield, UK
- Department of Biomedical Science, University of Sheffield, Sheffield, UK
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
| | - Ibrahim Boussaad
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
- Disease Modelling and Screening Platform (DMSP), Luxembourg Centre of Systems Biomedicine, University of Luxembourg & Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Javier Jarazo
- Developmental Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
- OrganoTherapeutics SARL, Luxembourg, Luxembourg
| | - Julia C Fitzgerald
- Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Paul Antony
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | - Marcus Keatinge
- Bateson Centre, University of Sheffield, Sheffield, UK
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
- Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, Scotland
| | | | - Jens C Schwamborn
- Developmental Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
- OrganoTherapeutics SARL, Luxembourg, Luxembourg
| | - Rejko Krüger
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
- Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg
- Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
| | - Marysia Placzek
- Bateson Centre, University of Sheffield, Sheffield, UK
- Department of Biomedical Science, University of Sheffield, Sheffield, UK
| | - Oliver Bandmann
- Bateson Centre, University of Sheffield, Sheffield, UK.
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
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15
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Regensburger M, Stemick J, Masliah E, Kohl Z, Winner B. Intracellular A53T Mutant α-Synuclein Impairs Adult Hippocampal Newborn Neuron Integration. Front Cell Dev Biol 2020; 8:561963. [PMID: 33262984 PMCID: PMC7686440 DOI: 10.3389/fcell.2020.561963] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 10/23/2020] [Indexed: 12/21/2022] Open
Abstract
Dendritic dysfunction is an early event in α-synuclein (α-syn) mediated neurodegeneration. Altered postsynaptic potential and loss of dendritic spines have been observed in different in vitro and in vivo models of synucleinopathies. The integration of newborn neurons into the hippocampus offers the possibility to study dendrite and spine formation in an adult environment. Specifically, survival of hippocampal adult newborn neurons is regulated by synaptic input and was reduced in a mouse model transgenic for human A53T mutant α-syn. We thus hypothesized that dendritic integration of newborn neurons is impaired in the adult hippocampus of A53T mice. We analyzed dendritic morphology of adult hippocampal neurons 1 month after retroviral labeling. Dendrite length was unchanged in the dentate gyrus of A53T transgenic mice. However, spine density and mushroom spine density of newborn neurons were severely decreased. In this mouse model, transgenic α-syn was expressed both within newborn neurons and within their environment. To specifically determine the cell autonomous effects, we analyzed cell-intrinsic overexpression of A53T α-syn using a retrovirus. Since A53T α-syn overexpressing newborn neurons exhibited decreased spine density 1 month after labeling, we conclude that cell-intrinsic A53T α-syn impairs postsynaptic integration of adult hippocampal newborn neurons. Our findings further support the role of postsynaptic degeneration as an early feature in synucleinopathies and provide a model system to study underlying mechanisms.
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Affiliation(s)
- Martin Regensburger
- Department of Stem Cell Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.,Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.,Center for Rare Diseases Erlangen (ZSEER), University Hospital Erlangen, Erlangen, Germany
| | - Judith Stemick
- Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Eliezer Masliah
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States.,Division of Neuroscience and Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States
| | - Zacharias Kohl
- Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.,Department of Neurology, University of Regensburg, Regensburg, Germany
| | - Beate Winner
- Department of Stem Cell Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.,Center for Rare Diseases Erlangen (ZSEER), University Hospital Erlangen, Erlangen, Germany
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16
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Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration. Int J Mol Sci 2020; 21:ijms21186875. [PMID: 32961703 PMCID: PMC7555074 DOI: 10.3390/ijms21186875] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells play key roles in maintaining brain homeostasis and regulating brain immune responses. They continuously scan and sense the brain environment to detect any occurring changes. Upon detection of a signal related to physiological or pathological processes, the cells are activated and transform to an amoeboid-like phenotype, mounting adequate responses that range from phagocytosis to secretion of inflammatory and trophic factors. The overwhelming evidence suggests that microglia are crucially implicated in influencing neuronal proliferation and differentiation, as well as synaptic connections, and thereby cognitive and behavioral functions. Here, we review the role of microglia in adult neurogenesis under physiological conditions, and how this role is affected in neurodegenerative diseases.
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17
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Zhao X, van Praag H. Steps towards standardized quantification of adult neurogenesis. Nat Commun 2020; 11:4275. [PMID: 32848155 PMCID: PMC7450090 DOI: 10.1038/s41467-020-18046-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 08/03/2020] [Indexed: 02/07/2023] Open
Abstract
New neurons are generated in adult mammals. Adult hippocampal neurogenesis is considered to play an important role in cognition and mental health. The number and properties of newly born neurons are regulatable by a broad range of physiological and pathological conditions. To begin to understand the underlying cellular mechanisms and functional relevance of adult neurogenesis, many studies rely on quantification of adult-born neurons. However, lack of standardized methods to quantify new neurons is impeding research reproducibility across laboratories. Here, we review the importance of stereology, and propose why and how it should be applied to the study of adult neurogenesis.
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Affiliation(s)
- Xinyu Zhao
- Waisman Center and University of Wisconsin-Madison, Madison, WI, 53705, USA.
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, USA.
| | - Henriette van Praag
- Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, 33458, USA.
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18
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The Role of Alpha-Synuclein and Other Parkinson's Genes in Neurodevelopmental and Neurodegenerative Disorders. Int J Mol Sci 2020; 21:ijms21165724. [PMID: 32785033 PMCID: PMC7460874 DOI: 10.3390/ijms21165724] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/29/2020] [Accepted: 08/08/2020] [Indexed: 12/13/2022] Open
Abstract
Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson's disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
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19
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Marschallinger J, Altendorfer B, Rockenstein E, Holztrattner M, Garnweidner-Raith J, Pillichshammer N, Leister I, Hutter-Paier B, Strempfl K, Unger MS, Chishty M, Felder T, Johnson M, Attems J, Masliah E, Aigner L. The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies. Neurotherapeutics 2020; 17:1061-1074. [PMID: 32072462 PMCID: PMC7609773 DOI: 10.1007/s13311-020-00836-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blocking leukotrienes through Montelukast, a leukotriene receptor antagonist and approved anti-asthmatic drug, might alleviate pathology and restore cognitive functions. Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was indeed elevated in brains with DLB. Treatment of cognitively deficient human alpha-synuclein overexpressing transgenic mice with Montelukast restored memory. Montelukast treatment resulted in modulation of beclin-1 expression, a marker for autophagy, and in a reduction in the human alpha-synulcein load in the transgenic mice. Reducing the protein aggregation load in neurodegenerative diseases might be a novel model of action of Montelukast. Moreover, this work presents leukotriene signaling as a potential drug target for DLB and shows that Montelukast might be a promising drug candidate for future DLB therapy development.
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Affiliation(s)
- Julia Marschallinger
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - Barbara Altendorfer
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - Edward Rockenstein
- Department of Neuroscience, School of Medicine, University of California San Diego, San Diego, USA
| | - Miriam Holztrattner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - Julia Garnweidner-Raith
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - Nadine Pillichshammer
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - Iris Leister
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | | | - Katharina Strempfl
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
- QPS Austria GmbH, Neuropharmacology, Grambach, Austria
| | - Michael S Unger
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | | | - Thomas Felder
- Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Mary Johnson
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Johannes Attems
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Eliezer Masliah
- Department of Neuroscience, School of Medicine, University of California San Diego, San Diego, USA
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria.
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
- Austrian Cluster for Tissue Regeneration, Vienna, Austria.
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20
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Taguchi K, Watanabe Y, Tsujimura A, Tanaka M. α-Synuclein Promotes Maturation of Immature Juxtaglomerular Neurons in the Mouse Olfactory Bulb. Mol Neurobiol 2019; 57:1291-1304. [PMID: 31722091 DOI: 10.1007/s12035-019-01814-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 10/11/2019] [Indexed: 01/02/2023]
Abstract
α-Synuclein (αSyn), the major constituent of Lewy bodies and Lewy neurites, is generally expressed in presynapses and is involved in synaptic function. However, we previously demonstrated that some neurons, including those in the olfactory bulb, show high αSyn expression levels in the cell body under normal conditions. αSyn is also known to be important for adult neurogenesis. Thus, in present study, we examined the role of αSyn in juxtaglomerular neurons (JGNs) with high αSyn expression in the mouse olfactory bulb. Most αSyn-enriched JGNs expressed sex-determining region Y-box 2 (Sox2), which functions to maintain neural immature identity. Interestingly, in αSyn homozygous (-/-) knockout (KO) mice, Sox2-positive JGNs were significantly increased compared with heterozygous (+/-) KO mice. Following global brain ischemia using wild-type mice, there was also a significant decrease in Sox2-positive JGNs, and in the co-expression ratio of Sox2 in αSyn-enriched JGNs. By contrast, the co-expression ratio of neuronal nuclei (NeuN, mature neuronal marker) was significantly increased in αSyn-enriched JGNs. However, this ischemia-induced decrease of Sox2-positive JGNs was not observed in αSyn homozygous KO mice. Overall, these data suggest that αSyn functions to promote the maturation of immature JGNs in the mouse olfactory bulb.
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Affiliation(s)
- Katsutoshi Taguchi
- Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto, 602-8566, Japan
| | - Yoshihisa Watanabe
- Department of Basic Geriatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Tsujimura
- Department of Basic Geriatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto, 602-8566, Japan
| | - Masaki Tanaka
- Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto, 602-8566, Japan.
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21
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Constitutive PGC-1α overexpression in skeletal muscle does not protect from age-dependent decline in neurogenesis. Sci Rep 2019; 9:12320. [PMID: 31444397 PMCID: PMC6707251 DOI: 10.1038/s41598-019-48795-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 07/29/2019] [Indexed: 01/26/2023] Open
Abstract
Aerobic exercise prevents age-dependent decline in cognition and hippocampal neurogenesis. The transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) mediates many of the exercise-induced benefits in skeletal muscle, including the release of factors into the circulation with neurotrophic effects. We use a transgenic mouse model with muscle-specific overexpression of PGC-1α to study the contribution of chronic muscle activation on exercise-induced effects on hippocampal neurogenesis in aging. Young and old transgenic and wild type animals of both sexes displayed a robust age-related reduction in newborn BrdU+-cells, immature neurons (DCX+-cells) and new mature BrdU+/NeuN+-neurons in the dentate gyrus. No differences were detected between genotypes or sexes. Analysis of serum proteins showed a tendency towards increased levels of myokines and reduced levels of pro-inflammatory cytokines for transgenic animals, but only musclin was found to be significantly up-regulated in transgenic animals. We conclude that constitutive muscular overexpression of PGC-1α, despite potent systemic changes, is insufficient for mimicking exercise-induced effects on hippocampal neurogenesis in aging. Continued studies are required to investigate the complex molecular mechanisms by which circulating signals could mediate exercise-induced effects on the central nervous system in disease and aging, with the aim of discovering new therapeutic possibilities for patients.
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22
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Zhang XM, Anwar S, Kim Y, Brown J, Comte I, Cai H, Cai NN, Wade-Martins R, Szele FG. The A30P α-synuclein mutation decreases subventricular zone proliferation. Hum Mol Genet 2019; 28:2283-2294. [PMID: 31267130 PMCID: PMC6606853 DOI: 10.1093/hmg/ddz057] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/05/2019] [Accepted: 03/14/2019] [Indexed: 01/11/2023] Open
Abstract
Parkinson's disease (PD) is associated with olfactory defects in addition to dopaminergic degeneration. Dopaminergic signalling is necessary for subventricular zone (SVZ) proliferation and olfactory bulb (OB) neurogenesis. Alpha-synuclein (α-syn or Snca) modulates dopaminergic neurotransmission, and SNCA mutations cause familial PD, but how α-syn and its mutations affect adult neurogenesis is unclear. To address this, we studied a bacterial artificial chromosome transgenic mouse expressing the A30P SNCA familial PD point mutation on an Snca-/- background. We confirmed that the SNCA-A30P transgene recapitulates endogenous α-syn expression patterns and levels by immunohistochemical detection of endogenous α-syn in a wild-type mouse and transgenic SNCA-A30P α-syn protein in the forebrain. The number of SVZ stem cells (BrdU+GFAP+) was decreased in SNCA-A30P mice, whereas proliferating (phospho-histone 3+) cells were decreased in Snca-/- and even more so in SNCA-A30P mice. Similarly, SNCA-A30P mice had fewer Mash1+ transit-amplifying SVZ progenitor cells but Snca-/- mice did not. These data suggest the A30P mutation aggravates the effect of Snca loss in the SVZ. Interestingly, calbindin+ and calretinin (CalR)+ periglomerular neurons were decreased in both Snca-/-, and SNCA-A30P mice but tyrosine hydroxylase+ periglomerular OB neurons were only decreased in Snca-/- mice. Cell death decreased in the OB granule layer of Snca-/- and SNCA-A30P mice. In the same region, CalR+ numbers increased in Snca-/- and SNCA-A30P mice. Thus, α-syn loss and human A30P SNCA decrease SVZ proliferation, cell death in the OB and differentially alter interneuron numbers. Similar disruptions in human neurogenesis may contribute to the olfactory deficits, which are observed in PD.
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Affiliation(s)
- Xue-Ming Zhang
- Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK
- College of Veterinary Medicine, Jilin University, Xi-an Road, Changchun, China
| | - Sabina Anwar
- Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK
- Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford, UK
| | - Yongsoo Kim
- Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK
| | - Jennifer Brown
- Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK
| | - Isabelle Comte
- Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK
| | - Huan Cai
- College of Veterinary Medicine, Jilin University, Xi-an Road, Changchun, China
| | - Ning-Ning Cai
- College of Veterinary Medicine, Jilin University, Xi-an Road, Changchun, China
| | - Richard Wade-Martins
- Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK
- Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford, UK
| | - Francis G Szele
- Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, UK
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23
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Stress-induced precocious aging in PD-patient iPSC-derived NSCs may underlie the pathophysiology of Parkinson's disease. Cell Death Dis 2019; 10:105. [PMID: 30718471 PMCID: PMC6362163 DOI: 10.1038/s41419-019-1313-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 12/09/2018] [Accepted: 12/12/2018] [Indexed: 12/17/2022]
Abstract
Parkinson’s disease (PD) is an aging-related degenerative disorder arisen from the loss of dopaminergic neurons in substantia nigra. Although many genetic mutations have been implicated to be genetically linked to PD, the low incidence of familial PD carried with mutations suggests that there must be other factors such as oxidative stress, mitochondrial dysfunction, accumulation of misfolded proteins, and enhanced inflammation, which are contributable to the pathophysiology of PD. The major efforts of current research have been devoted to unravel the toxic effect of multiple factors, which directly cause the degeneration of dopaminergic neurons in adulthood. Until recently, several studies have demonstrated that NSCs had compromised proliferation and differentiation capacity in PD animal models or PD patient-derived iPS models, suggesting that the pathology of PD may be rooted in some cellular aberrations at early developmental stage but the mechanism remains to be elusive. Based on the early-onset PD patient-specific iPSCs, we found that PD-patient iPSC-derived NSCs were more susceptible to stress and became functionally compromised by radiation or oxidative insults. We further unraveled that stress-induced SIRT1 downregulation leading to autophagic dysfunction, which were responsible for these deficits in PD-NSCs. Mechanistically, we demonstrated that stress-induced activation of p38 MAPK suppressed SIRT1 expression, which in turn augmented the acetylation of multiple ATG proteins of autophagic complex and eventually led to autophagic deficits. Our studies suggest that early developmental deficits may, at least partially, contribute to the pathology of PD and provide a new avenue for developing better therapeutic interventions to PD.
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The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry 2019; 24:67-87. [PMID: 29679070 PMCID: PMC6195869 DOI: 10.1038/s41380-018-0036-2] [Citation(s) in RCA: 447] [Impact Index Per Article: 74.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 01/15/2018] [Accepted: 01/31/2018] [Indexed: 12/18/2022]
Abstract
Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions, such as memory encoding and mood regulation. In addition, several brain diseases, such as neurological diseases and mood disorders, have deleterious effects on adult hippocampal neurogenesis, and some symptoms of those diseases can be partially explained by the dysregulation of adult hippocampal neurogenesis. Here we review a possible link between the physiological functions of adult-born neurons and their roles in pathological conditions.
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Zasso J, Ahmed M, Cutarelli A, Conti L. Inducible Alpha-Synuclein Expression Affects Human Neural Stem Cells' Behavior. Stem Cells Dev 2018; 27:985-994. [PMID: 29669468 DOI: 10.1089/scd.2018.0011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Converging evidence suggest that levels of alpha-synuclein (aSyn) expression play a critical role in Parkinson's disease (PD). Several mutations of the SNCA gene, encoding for aSyn have been associated to either the familial or the sporadic forms of PD. Nonetheless, the mechanism underlying wild-type aSyn-mediated neurotoxicity in neuronal cells as well as its specific driving role in PD pathogenesis has yet to be fully clarified. In this view, the development of proper in vitro cellular systems is a crucial step. In this study, we present a novel human Tet-on human neural stem cell (hNSC) line, in which aSyn timing and level of expression can be tightly experimentally tuned. Induction of aSyn in self-renewing hNSCs leads to progressive formation of aSyn aggregates and impairs their proliferation and cell survival. Furthermore, aSyn induction during the neuronal differentiation process results in reduced neuronal differentiation and increased number of astrocytes and undifferentiated cells in culture. Finally, acute aSyn induction in hNSC-derived dopaminergic neuronal cultures results in cell toxicity. This novel conditional in vitro cell model system may be a valuable tool for dissecting of aSyn pathogenic effects in hNSCs and neurons and in developing new potential therapeutic strategies.
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Affiliation(s)
- Jacopo Zasso
- Centre for Integrative Biology-CIBIO, Università degli Studi di Trento , Trento, Italy
| | - Mastad Ahmed
- Centre for Integrative Biology-CIBIO, Università degli Studi di Trento , Trento, Italy
| | - Alessandro Cutarelli
- Centre for Integrative Biology-CIBIO, Università degli Studi di Trento , Trento, Italy
| | - Luciano Conti
- Centre for Integrative Biology-CIBIO, Università degli Studi di Trento , Trento, Italy
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26
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Crowley EK, Nolan YM, Sullivan AM. Neuroprotective effects of voluntary running on cognitive dysfunction in an α-synuclein rat model of Parkinson's disease. Neurobiol Aging 2018; 65:60-68. [PMID: 29407467 DOI: 10.1016/j.neurobiolaging.2018.01.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 12/21/2017] [Accepted: 01/17/2018] [Indexed: 02/04/2023]
Abstract
Parkinson's disease (PD) is no longer primarily classified as a motor disorder due to increasing recognition of the impact on patients of several nonmotor PD symptoms, including cognitive dysfunction. These nonmotor symptoms are highly prevalent and greatly affect the quality of life of patients with PD, and so, therapeutic interventions to alleviate these symptoms are urgently needed. The aim of this study was to investigate the potential neuroprotective effects of voluntary running on cognitive dysfunction in an adeno-associated virus-α-synuclein rat model of PD. Bilateral intranigral administration of adeno-associated virus-α-synuclein was found to induce motor dysfunction and a significant loss of nigral dopaminergic neurons, neither of which were rescued by voluntary running. Overexpression of α-synuclein also resulted in significant impairment on hippocampal neurogenesis-dependent pattern separation, a cognitive task; this was rescued by voluntary running. This was substantiated by an effect of running on neurogenesis levels in the dorsal dentate gyrus, suggesting that the functional effects of running on pattern separation were mediated via increased neurogenesis.
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Affiliation(s)
- Erin K Crowley
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Yvonne M Nolan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Aideen M Sullivan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland.
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Kim S, Lim J, Bang Y, Moon J, Kwon MS, Hong JT, Jeon J, Seo H, Choi HJ. Alpha-Synuclein Suppresses Retinoic Acid-Induced Neuronal Differentiation by Targeting the Glycogen Synthase Kinase-3β/β-Catenin Signaling Pathway. Mol Neurobiol 2018; 55:1607-1619. [PMID: 28190238 DOI: 10.1007/s12035-016-0370-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 12/28/2016] [Indexed: 11/27/2022]
Abstract
Alpha-synuclein (α-SYN) is expressed during neuronal development and is mainly involved in the modulation of synaptic transmission. Missense mutations and amplifications of this gene have been associated with the pathogenesis of Parkinson's disease. Here, we evaluate whether α-SYN plays a detrimental role in the phenotypic and morphological regulation of neurons. We also identify the underlying mechanisms of this process in all-trans-retinoic acid (RA)-induced differentiated SH-SY5Y cells, which represents dopaminergic (DAergic) phenotype. Our results indicate that overexpression of wild-type or mutant A53T α-SYN attenuated the RA-induced upregulation of tyrosine hydroxylase and dopamine transporter as well as neurite outgrowth in SH-SY5Y cells. In addition, GSK-3β inactivation and downstream β-catenin stabilization were associated with RA-induced differentiation, which was attenuated by α-SYN. Moreover, protein phosphatase 2A was positively regulated by α-SYN and was implicated in the α-SYN-mediated interference with RA signaling. The results obtained from SH-SY5Y cells were verified in primary cultures of mesencephalic DAergic neurons from A53T α-SYN transgenic mice, which represent high levels of α-SYN and protein phosphatase 2A in the midbrain. The number and length of neurites in tyrosine hydroxylase-positive as well as Tau-positive cells from A53T α-SYN transgenic mice were significantly lower than those in littermate controls. The current results provide novel insight into the role of α-SYN in the regulation of neuronal differentiation, including DAergic neurons. Identifying the signaling pathway involved in the α-SYN-mediated dysregulation of neuronal differentiation could lead to a better understanding of the developmental processes underlying α-SYN-related pathologies and facilitate the discovery of specifically targeted therapeutics.
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Affiliation(s)
- Sasuk Kim
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea
| | - Juhee Lim
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea
| | - Yeojin Bang
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea
| | - Jisook Moon
- Department of Bioengineering, College of Life Science, CHA University, Seongnam, 13488, Republic of Korea
| | - Min-Soo Kwon
- Department of Pharmacology, School of Medicine, CHA University, Seongnam, 13488, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Jeha Jeon
- Department of Molecular and Life Sciences, Hanyang University, Ansan, 15588, Republic of Korea
| | - Hyemyung Seo
- Department of Molecular and Life Sciences, Hanyang University, Ansan, 15588, Republic of Korea
| | - Hyun Jin Choi
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea.
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Synaptic Regulator α-Synuclein in Dopaminergic Fibers Is Essentially Required for the Maintenance of Subependymal Neural Stem Cells. J Neurosci 2017; 38:814-825. [PMID: 29217686 DOI: 10.1523/jneurosci.2276-17.2017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 11/10/2017] [Accepted: 11/28/2017] [Indexed: 01/11/2023] Open
Abstract
Synaptic protein α-synuclein (α-SYN) modulates neurotransmission in a complex and poorly understood manner and aggregates in the cytoplasm of degenerating neurons in Parkinson's disease. Here, we report that α-SYN present in dopaminergic nigral afferents is essential for the normal cycling and maintenance of neural stem cells (NSCs) in the brain subependymal zone of adult male and female mice. We also show that premature senescence of adult NSCs into non-neurogenic astrocytes in mice lacking α-SYN resembles the effects of dopaminergic fiber degeneration resulting from chronic exposure to 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine or intranigral inoculation of aggregated toxic α-SYN. Interestingly, NSC loss in α-SYN-deficient mice can be prevented by viral delivery of human α-SYN into their sustantia nigra or by treatment with l-DOPA, suggesting that α-SYN regulates dopamine availability to NSCs. Our data indicate that α-SYN, present in dopaminergic nerve terminals supplying the subependymal zone, acts as a niche component to sustain the neurogenic potential of adult NSCs and identify α-SYN and DA as potential targets to ameliorate neurogenic defects in the aging and diseased brain.SIGNIFICANCE STATEMENT We report an essential role for the protein α-synuclein present in dopaminergic nigral afferents in the regulation of adult neural stem cell maintenance, identifying the first synaptic regulator with an implication in stem cell niche biology. Although the exact role of α-synuclein in neural transmission is not completely clear, our results indicate that it is required for stemness and the preservation of neurogenic potential in concert with dopamine.
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Regensburger M, Schreglmann SR, Stoll S, Rockenstein E, Loskarn S, Xiang W, Masliah E, Winner B. Oligomer-prone E57K-mutant alpha-synuclein exacerbates integration deficit of adult hippocampal newborn neurons in transgenic mice. Brain Struct Funct 2017; 223:1357-1368. [PMID: 29124353 PMCID: PMC5869938 DOI: 10.1007/s00429-017-1561-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 11/02/2017] [Indexed: 11/26/2022]
Abstract
In the adult mammalian hippocampus, new neurons are constantly added to the dentate gyrus. Adult neurogenesis is impaired in several neurodegenerative mouse models including α-synuclein (a-syn) transgenic mice. Among different a-syn species, a-syn oligomers were reported to be the most toxic species for neurons. Here, we studied the impact of wild-type vs. oligomer-prone a-syn on neurogenesis. We compared the wild-type a-syn transgenic mouse model (Thy1-WTS) to its equivalent transgenic for oligomer-prone E57K-mutant a-syn (Thy1-E57K). Transgenic a-syn was highly expressed within the hippocampus of both models, but was not present within adult neural stem cells and neuroblasts. Proliferation and survival of newly generated neurons were unchanged in both transgenic models. Thy1-WTS showed a minor integration deficit regarding mushroom spine density of newborn neurons, whereas Thy1-E57K exhibited a severe reduction of all spines. We conclude that cell-extrinsic a-syn impairs mushroom spine formation of adult newborn neurons and that oligomer-prone a-syn exacerbates this integration deficit. Moreover, our data suggest that a-syn reduces the survival of newborn neurons by a cell-intrinsic mechanism during the early neuroblast development. The finding of increased spine pathology in Thy1-E57K is a new pathogenic function of oligomeric a-syn and precedes overt neurodegeneration. Thus, it may constitute a readout for therapeutic approaches.
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Affiliation(s)
- Martin Regensburger
- Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- IZKF Junior Research Group III, and BMBF Research Group Neuroscience, FAU, Erlangen, Germany
- Department of Neurology, FAU, Erlangen, Germany
| | - Sebastian R Schreglmann
- School of Medicine, University of Regensburg, Regensburg, Germany
- Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, London, UK
| | - Svenja Stoll
- Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- IZKF Junior Research Group III, and BMBF Research Group Neuroscience, FAU, Erlangen, Germany
| | - Edward Rockenstein
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
| | - Sandra Loskarn
- Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- IZKF Junior Research Group III, and BMBF Research Group Neuroscience, FAU, Erlangen, Germany
- Department of Neurology, FAU, Erlangen, Germany
| | - Wei Xiang
- Institute of Biochemistry, FAU, Erlangen, Germany
| | - Eliezer Masliah
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
| | - Beate Winner
- Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
- IZKF Junior Research Group III, and BMBF Research Group Neuroscience, FAU, Erlangen, Germany.
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Pino A, Fumagalli G, Bifari F, Decimo I. New neurons in adult brain: distribution, molecular mechanisms and therapies. Biochem Pharmacol 2017; 141:4-22. [PMID: 28690140 DOI: 10.1016/j.bcp.2017.07.003] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 07/05/2017] [Indexed: 12/16/2022]
Abstract
"Are new neurons added in the adult mammalian brain?" "Do neural stem cells activate following CNS diseases?" "How can we modulate their activation to promote recovery?" Recent findings in the field provide novel insights for addressing these questions from a new perspective. In this review, we will summarize the current knowledge about adult neurogenesis and neural stem cell niches in healthy and pathological conditions. We will first overview the milestones that have led to the discovery of the classical ventricular and hippocampal neural stem cell niches. In adult brain, new neurons originate from proliferating neural precursors located in the subventricular zone of the lateral ventricles and in the subgranular zone of the hippocampus. However, recent findings suggest that new neuronal cells can be added to the adult brain by direct differentiation (e.g., without cell proliferation) from either quiescent neural precursors or non-neuronal cells undergoing conversion or reprogramming to neuronal fate. Accordingly, in this review we will also address critical aspects of the newly described mechanisms of quiescence and direct conversion as well as the more canonical activation of the neurogenic niches and neuroblast reservoirs in pathological conditions. Finally, we will outline the critical elements involved in neural progenitor proliferation, neuroblast migration and differentiation and discuss their potential as targets for the development of novel therapeutic drugs for neurodegenerative diseases.
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Affiliation(s)
- Annachiara Pino
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Italy
| | - Guido Fumagalli
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Italy
| | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Italy.
| | - Ilaria Decimo
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Italy.
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31
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Yang W, Yu S. Synucleinopathies: common features and hippocampal manifestations. Cell Mol Life Sci 2017; 74:1485-1501. [PMID: 27826641 PMCID: PMC11107502 DOI: 10.1007/s00018-016-2411-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 10/31/2016] [Accepted: 11/03/2016] [Indexed: 01/08/2023]
Abstract
Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA) are three major synucleinopathies characterized by α-synuclein-containing inclusions in the brains of patients. Because the cell types and brain structures that are affected vary markedly between the disorders, the patients have different clinical manifestations in addition to some overlapping symptoms, which are the basis for differential diagnosis. Cognitive impairment and depression associated with hippocampal dysfunction are frequently observed in these disorders. While various α-synuclein-containing inclusions are found in the hippocampal formation, increasing evidence supports that small α-synuclein aggregates or oligomers may be the real culprit, causing deficits in neurotransmission and neurogenesis in the hippocampus and related brain regions, which constitute the major mechanism for the hippocampal dysfunctions and associated neuropsychiatric manifestations in synucleinopathies.
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Affiliation(s)
- Weiwei Yang
- Department of Neurobiology, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China
| | - Shun Yu
- Department of Neurobiology, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China.
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
- Beijing Key Laboratory for Parkinson's Disease, Beijing, China.
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32
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Unger MS, Marschallinger J, Kaindl J, Höfling C, Rossner S, Heneka MT, Van der Linden A, Aigner L. Early Changes in Hippocampal Neurogenesis in Transgenic Mouse Models for Alzheimer's Disease. Mol Neurobiol 2016; 53:5796-806. [PMID: 27544234 PMCID: PMC5012146 DOI: 10.1007/s12035-016-0018-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 08/01/2016] [Indexed: 12/01/2022]
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the Western world and is characterized by a progressive loss of cognitive functions leading to dementia. One major histopathological hallmark of AD is the formation of amyloid-beta plaques, which is reproduced in numerous transgenic animal models overexpressing pathogenic forms of amyloid precursor protein (APP). In human AD and in transgenic amyloid plaque mouse models, several studies report altered rates of adult neurogenesis, i.e. the formation of new neurons from neural stem and progenitor cells, and impaired neurogenesis has also been attributed to contribute to the cognitive decline in AD. So far, changes in neurogenesis have largely been considered to be a consequence of the plaque pathology. Therefore, possible alterations in neurogenesis before plaque formation or in prodromal AD have been largely ignored. Here, we analysed adult hippocampal neurogenesis in amyloidogenic mouse models of AD at different points before and during plaque progression. We found prominent alterations of hippocampal neurogenesis before plaque formation. Survival of newly generated cells and the production of new neurons were already compromised at this stage. Moreover and surprisingly, proliferation of doublecortin (DCX) expressing neuroblasts was significantly and specifically elevated during the pre-plaque stage in the APP-PS1 model, while the Nestin-expressing stem cell population was unaffected. In summary, changes in neurogenesis are evident already before plaque deposition and might contribute to well-known early hippocampal dysfunctions in prodromal AD such as hippocampal overactivity.
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Affiliation(s)
- M S Unger
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - J Marschallinger
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - J Kaindl
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - C Höfling
- Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany
| | - S Rossner
- Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany
| | - Michael T Heneka
- Clinical Neuroscience, Department of Neurology, University of Bonn, Bonn, Germany
| | - A Van der Linden
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria.
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
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Marxreiter F, Storch A, Winkler J. [Cellular replacement strategies and adult neurogenesis in idiopathic Parkinson's disease]. DER NERVENARZT 2016; 87:805-13. [PMID: 27389601 DOI: 10.1007/s00115-016-0157-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Parkinson's disease (PD) is the most common age-related movement disorder and characterized by slowly progressive neurodegeneration resulting in motor symptoms, such as bradykinesia, rigidity, tremor and postural instability. Moreover, non-motor symptoms, such as hyposmia, anxiety and depression reduce the quality of life in PD. Motor symptoms are associated with a distinct striatal dopaminergic deficit resulting from axonal dysfunction and neuronal loss in the substantia nigra (SN). Recent progress in stem cell technology allows the optimization of cellular transplantation strategies in order to alleviate the motor deficit, which potentially leads to a reactivation of this therapeutic strategy. Besides neurodegenerative processes impaired adult neurogenesis and consequentially reduced endogenous cellular plasticity may play an important role in PD. This article discusses the notion that non-motor symptoms in PD may partly be explained by reduced adult neurogenesis in the olfactory bulb and hippocampus.
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Affiliation(s)
- F Marxreiter
- Abteilung für Molekulare Neurologie, Universitätsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Deutschland
| | - A Storch
- Klinik und Poliklinik für Neurologie, Universität Rostock, Gehlsheimer Straße 20, 18147, Rostock, Deutschland.,Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock, Gehlsheimer Straße 20, 18147, Rostock, Deutschland
| | - J Winkler
- Abteilung für Molekulare Neurologie, Universitätsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Deutschland.
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Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model. J Neuroinflammation 2016; 13:174. [PMID: 27364890 PMCID: PMC4929755 DOI: 10.1186/s12974-016-0632-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 06/20/2016] [Indexed: 01/25/2023] Open
Abstract
Background Synucleinopathies comprise a group of neurodegenerative diseases associated with abnormal accumulation of α-synuclein. One of the key factors that contribute to the progression of synucleinopathies is neuroinflammation. However, the role of lymphocytes in synucleinopathies like Parkinson’s disease (PD) remains largely unclear. Methods To investigate how lymphocytes impact synucleinopathies, human wild-type α-synuclein (WTS) transgenic mice were crossed with mice lacking mature lymphocytes (Rag2−/−). In this in vivo model, we quantified α-synuclein aggregation in the substantia nigra (SN) and striatum and determined the numbers of innate and adaptive immune cells in the central nervous system (CNS). The activation state of resident and infiltrated CNS myeloid cells (M1 vs. M2) was further classified by gene and protein expression analyses. The impact of T and B lymphocytes on the phagocytic activity of microglia in the presence of α-synuclein aggregates was addressed in BV2 microglia in vitro. Results Compared to WTS+ Rag2+/+ mice, where T but not B lymphocytes infiltrated the CNS, decreased amounts of α-synuclein aggregates were found in WTS+ Rag2−/− mice devoid of mature lymphocytes. The presence of T lymphocytes did not alter the number of Iba1+ microglia but increased the frequency of the CD11b+ CD45hi population in the CNS, indicative of an increased number of infiltrated macrophages. Moreover, the M1 phenotype was more prominent in WTS+ Rag2+/+ mice, whereas the M2 activation state was dominating in the absence of lymphocytes in WTS+ Rag2−/− mice. In vitro, in the presence of T but not B lymphocytes, significantly less α-synuclein was phagocytosed by BV2 microglia, further supporting the prevalence of the M1 phenotype in the presence of T lymphocytes. Conclusions Peripheral T lymphocytes strongly contribute to increased α-synuclein pathology via modulation of CNS myeloid cell function. In the presence of T lymphocytes, microglia phagocytosis of aggregated α-synuclein is reduced, which increases the severity of synucleinopathy. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0632-5) contains supplementary material, which is available to authorized users.
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Expression of the Parkinson’s Disease-Associated Gene Alpha-Synuclein is Regulated by the Neuronal Cell Fate Determinant TRIM32. Mol Neurobiol 2016; 54:4257-4270. [DOI: 10.1007/s12035-016-9989-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 06/14/2016] [Indexed: 12/27/2022]
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36
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Zhang L, Deng J, Pan Q, Zhan Y, Fan JB, Zhang K, Zhang Z. Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease. J Genet Genomics 2016; 43:587-592. [PMID: 27692691 DOI: 10.1016/j.jgg.2016.05.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 04/05/2016] [Accepted: 05/09/2016] [Indexed: 12/11/2022]
Abstract
Parkinson disease (PD) is a progressive neurodegenerative movement disorder. Both environmental and genetic factors play important roles in PD etiology. A number of environmental toxins cause parkinsonism in human and animal models. Genetic studies of rare early onset familial PD cases resulted in identification of disease-linked mutations in multiple genes. Nevertheless, the potential interaction between environment and genetics in PD pathogenesis remains largely unknown. We hypothesized that environmental factors induce abnormal epigenetic regulation that is involved in the pathogenesis of both familial and sporadic PD. We determined the global methylation status of 80,000-110,000 CpG sites in each of the five sporadic PD patient brains and five age and postmodern interval matched control brains utilizing bisulfite padlock sequencing. Multiple genes involved in neurogenesis, particularly the ones in the Wnt signaling pathway, were hypermethylated in PD brains compared to their matched control brains. Consistent with the DNA methylation changes, marked reduction of protein expression was observed for four Wnt and neurogenesis related genes (FOXC1, NEURG2, SPRY1, and CTNNB1) in midbrain dopaminergic (DA) neurons of PD. The treatment of low concentration of 1-methyl-4-phenylpyridinium (MPP+) for cells resulted in downregulation of Wnt related genes. The study revealed an important link between the epigenetic disregulation of Wnt signaling and the pathogenesis and progression of PD.
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Affiliation(s)
- Lusi Zhang
- Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China
| | - Jie Deng
- Department of Bioengineering, University of California at San Diego, California 92093, USA
| | - Qian Pan
- Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China
| | - Yan Zhan
- Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China
| | - Jian-Bing Fan
- Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China; AnchorDx Corporation, International Bio-island, Guangzhou 510300, China
| | - Kun Zhang
- Department of Bioengineering, University of California at San Diego, California 92093, USA.
| | - Zhuohua Zhang
- Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China.
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Eyre HA, Eskin A, Nelson SF, St. Cyr NM, Siddarth P, Baune BT, Lavretsky H. Genomic predictors of remission to antidepressant treatment in geriatric depression using genome-wide expression analyses: a pilot study. Int J Geriatr Psychiatry 2016; 31:510-7. [PMID: 26471432 PMCID: PMC5567872 DOI: 10.1002/gps.4356] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 08/21/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE This first pilot study of genome-wide expression as predictor of antidepressant response in late-life depression examined genome-wide transcriptional profiles in a randomized placebo-controlled trial of combined methylphenidate and citalopram. METHODS Genome-wide transcriptional profiles were examined in peripheral blood leukocytes sampled at baseline and 16 weeks from 35 older adults with major depression, who were randomized to methylphenidate + citalopram, citalopram + placebo, or methylphenidate + placebo. Methylphenidate doses ranged between 10 and 40 mg/day, and citalopram doses ranged between 20 and 60 mg/day. Remission was defined as Hamilton Depression Rating Scale score of 6 or below. Early remission was achieved in the first 4 weeks of treatment. We hypothesized that differential gene expression at baseline can predict antidepressant response. RESULTS We analyzed gene expression in 24 remitters and 11 non-remitters. At baseline, we found three genes showing higher expression in all remitters versus non-remitters that satisfied the established level of significance: a fold change of 2 and p-value of 0.05 that included HLA-DRB5, SELENBP1, and LOC388588. Two gene transcripts showed higher expression in early remitters at baseline compared with non-remitters. The first gene was CA1 carbonic anhydrase gene, on chromosome 8 involved in respiratory function (fold change 2.54; p = 0.03). The second gene was the SNCA-α-synuclein gene, implicated, which binds to dopamine transporter (fold change 2.1; p = 0.03). CONCLUSIONS Remission to antidepressants in geriatric depression may be associated with a particular gene expression profile in monoaminergic and metabolic pathways and needs to be replicated in a larger sample.
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Affiliation(s)
- Harris A. Eyre
- Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia,UCLA Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA
| | - Ascia Eskin
- Department of Human Genetics, UCLA, Los Angeles, CA, USA
| | | | - Natalie M. St. Cyr
- UCLA Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA
| | - Prabha Siddarth
- UCLA Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA
| | - Bernhard T. Baune
- Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia
| | - Helen Lavretsky
- UCLA Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA
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Ataxin-1 regulates proliferation of hippocampal neural precursors. Neuroscience 2016; 322:54-65. [PMID: 26876606 DOI: 10.1016/j.neuroscience.2016.02.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 01/11/2016] [Accepted: 02/03/2016] [Indexed: 02/01/2023]
Abstract
Polyglutamine expansion in the protein ATAXIN-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), an inherited neurodegenerative disease characterized by motor deficits, cognitive impairment and depression. Although ubiquitously expressed, mutant ATXN1 causes neurodegeneration primarily in the cerebellum, which is responsible for the observed motor deficits. The role of ATXN1 outside of the cerebellum and the causes of cognitive deficits and depression in SCA1 are less understood. In this study, we demonstrate a novel role of ATXN1 in the hippocampus as a regulator of adult neurogenesis. Adult hippocampal neurogenesis is the process of generating new hippocampal neurons and is linked to cognition and mood. We found that loss of ATXN1 causes a decrease in hippocampal neurogenesis in ATXN1 null (Atxn1(-/-)) mice. This decrease was caused by reduced proliferation of neural precursors in the hippocampus of Atxn1(-/-) mice, and persisted even when Atxn1(-/-) hippocampal neural precursors were removed from their natural environment and grown in vitro, suggesting that ATXN1 affects proliferation in a cell-autonomous manner. Moreover, expression of ATXN1 with a pathological polyglutamine (polyQ) expansion in wild-type neural precursor cells inhibited their proliferation. Our data establish a novel role for ATXN1 in the hippocampus as an intrinsic regulator of precursor cell proliferation, and suggest a mechanism by which polyQ expansion and loss of ATXN1 affect hippocampal function, potentially contributing to cognitive deficits and depression. These results indicate that while depletion of ATXN1 is a promising therapeutic approach to treat the cerebellar aspects of SCA1, this approach should be employed with caution given the potential for side effects on hippocampal function with loss of wild-type ATXN1.
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Albright JE, Stojkovska I, Rahman AA, Brown CJ, Morrison BE. Nestin-positive/SOX2-negative cells mediate adult neurogenesis of nigral dopaminergic neurons in mice. Neurosci Lett 2016; 615:50-4. [PMID: 26806039 DOI: 10.1016/j.neulet.2016.01.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 01/11/2016] [Accepted: 01/13/2016] [Indexed: 01/23/2023]
Abstract
The primary clinical motor symptoms of Parkinson's disease (PD) result from loss of dopaminergic (DA) neurons in the substantia nigra (SN). Consequently, neurogenesis of this group of neurons in the adult brain has drawn considerable interest for the purpose of harnessing endogenous neurogenerative potential as well as devising better strategies for stem cell therapy for PD. However, the existence of adult neurogenesis for DA neurons within the SN remains controversial. To overcome technical and design limitations associated with previous studies, our group has developed a novel genetic mouse model for assessing adult nigral DA neurogenesis. This system utilizes transgenic mice that express a tamoxifen-activatable Cre recombinase (Cre(ERT2)) under the control of the neuronal progenitor cell promoters nestin or Sox2 leading to suppression of the DA neuron marker tyrosine hydroxylase (TH) via excision of exon 1 by flanking loxP sites in adult animals. This study reports that six months following initiation of a six week treatment with tamoxifen mice with nestin-mediated Th excision displayed a significant reduction in TH+ neurons in the SN. This finding indicates that nestin-expressing cells regenerate DA neurons within the SN of adult animals. Interestingly, no reduction was observed in TH+ cells following Sox2-mediated Th excision suggesting that a nestin+/SOX2- precursor cell population drives DA neurogenesis in the adult SN. This information represents a substantial leap in current knowledge of adult DA neurogenesis, will enable improved in vitro and in vivo modeling, as well as facilitate the harnessing of this process for therapeutic intervention for PD.
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Affiliation(s)
- Joshua E Albright
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA
| | - Iva Stojkovska
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA
| | - Abir A Rahman
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA; Biomolecular Ph.D. program, Boise State University, Boise, ID 83725, USA
| | - Connor J Brown
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA
| | - Brad E Morrison
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA; Biomolecular Ph.D. program, Boise State University, Boise, ID 83725, USA.
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Tilve S, Difato F, Chieregatti E. Cofilin 1 activation prevents the defects in axon elongation and guidance induced by extracellular alpha-synuclein. Sci Rep 2015; 5:16524. [PMID: 26558842 PMCID: PMC4642265 DOI: 10.1038/srep16524] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/15/2015] [Indexed: 12/20/2022] Open
Abstract
Impaired adult neurogenesis and axon traumatic injury participate in the severity of neurodegenerative diseases. Alpha-synuclein, a cytosolic protein involved in Parkinson's disease, may be released from neurons, suggesting a role for excess secreted alpha-synuclein in the onset and spread of the pathology. Here we provide evidence that long term exposure of young neurons to extracellular alpha-synuclein hampers axon elongation and growth cone turning. We show that actin turnover and the rate of movement of actin waves along the axon are altered, due to alpha-synuclein-induced inactivation of cofilin. Upon laser disruption of microfilaments, healing of axons is favored by the increased phosphorylation of cofilin, however, at later time points; the defect in neurite extension prevails, being lost the regulation of cofilin activity. Importantly, overexpression of the active form of cofilin in neurons exposed to alpha-synuclein is able to restore the movement of actin waves, physiological axon elongation and growth cone turning. Our study reveals the molecular basis of alpha-synuclein-driven deficits in growth and migration of newborn neurons, and in elongation and regeneration of adult neurons.
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Affiliation(s)
- Sharada Tilve
- Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Francesco Difato
- Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Evelina Chieregatti
- Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy
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Kohl Z, Ben Abdallah N, Vogelgsang J, Tischer L, Deusser J, Amato D, Anderson S, Müller CP, Riess O, Masliah E, Nuber S, Winkler J. Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson's disease. Neurobiol Dis 2015; 85:206-217. [PMID: 26523794 DOI: 10.1016/j.nbd.2015.10.021] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Revised: 10/20/2015] [Accepted: 10/27/2015] [Indexed: 12/24/2022] Open
Abstract
Parkinson's disease (PD) is a multisystem disorder, involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of alpha-synuclein, however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus may contribute to early non-motor symptoms such as anxiety and depression. The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating alpha-synuclein levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of human full-length alpha-synuclein on hippocampal cellular and synaptic plasticity, we used a recently generated BAC alpha-synuclein transgenic rat model showing important features of PD such as widespread and progressive alpha-synuclein aggregation pathology, dopamine loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of serotonin (5-HT) 1B receptor, decreased 5-HT neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/CA3 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, alpha-synuclein overexpression reduced proteins involved in vesicle release, in particular synapsin-1 and Rab3 interacting molecule (RIM3), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, BAC alpha-synuclein rats showed an early anxiety-like phenotype consisting of reduced exploratory behavior and feeding. Taken together, these findings imply that accumulating alpha-synuclein severely affects hippocampal neurogenesis paralleled by impaired 5-HT neurotransmission prior to the onset of aggregation pathology and overt motor deficits in this transgenic rat model of PD.
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Affiliation(s)
- Zacharias Kohl
- Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Nada Ben Abdallah
- Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Jonathan Vogelgsang
- Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Lucas Tischer
- Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Janina Deusser
- Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Davide Amato
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Scott Anderson
- Department of Neurosciences and Pathology, University of California, San Diego, La Jolla, USA
| | - Christian P Müller
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Olaf Riess
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Eliezer Masliah
- Department of Neurosciences and Pathology, University of California, San Diego, La Jolla, USA
| | - Silke Nuber
- Department of Neurosciences and Pathology, University of California, San Diego, La Jolla, USA; Department of Psychiatry, University of California, San Diego, La Jolla, USA; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
| | - Jürgen Winkler
- Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
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Schreglmann SR, Regensburger M, Rockenstein E, Masliah E, Xiang W, Winkler J, Winner B. The temporal expression pattern of alpha-synuclein modulates olfactory neurogenesis in transgenic mice. PLoS One 2015; 10:e0126261. [PMID: 25961568 PMCID: PMC4427489 DOI: 10.1371/journal.pone.0126261] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 03/31/2015] [Indexed: 12/11/2022] Open
Abstract
Background Adult neurogenesis mirrors the brain´s endogenous capacity to generate new neurons throughout life. In the subventricular zone/ olfactory bulb system adult neurogenesis is linked to physiological olfactory function and has been shown to be impaired in murine models of neuronal alpha-Synuclein overexpression. We analyzed the degree and temporo-spatial dynamics of adult olfactory bulb neurogenesis in transgenic mice expressing human wild-type alpha-Synuclein (WTS) under the murine Thy1 (mThy1) promoter, a model known to have a particularly high tg expression associated with impaired olfaction. Results Survival of newly generated neurons (NeuN-positive) in the olfactory bulb was unchanged in mThy1 transgenic animals. Due to decreased dopaminergic differentiation a reduction in new dopaminergic neurons within the olfactory bulb glomerular layer was present. This is in contrast to our previously published data on transgenic animals that express WTS under the control of the human platelet-derived growth factor β (PDGF) promoter, that display a widespread decrease in survival of newly generated neurons in regions of adult neurogenesis, resulting in a much more pronounced neurogenesis deficit. Temporal and quantitative expression analysis using immunofluorescence co-localization analysis and Western blots revealed that in comparison to PDGF transgenic animals, in mThy1 transgenic animals WTS is expressed from later stages of neuronal maturation only but at significantly higher levels both in the olfactory bulb and cortex. Conclusions The dissociation between higher absolute expression levels of alpha-Synuclein but less severe impact on adult olfactory neurogenesis in mThy1 transgenic mice highlights the importance of temporal expression characteristics of alpha-Synuclein on the maturation of newborn neurons.
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Affiliation(s)
| | - Martin Regensburger
- IZKF Junior Research Group III and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, FAU Erlangen-Nürnberg, Nikolaus-Fiebiger Center for Molecular Medicine, Erlangen, Germany
- Department of Neurology, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Edward Rockenstein
- Department of Neurosciences, University of California San Diego, La Jolla, California, CA, United States of America
- Department of Pathology, University of California San Diego, La Jolla, California, CA, United States of America
| | - Eliezer Masliah
- Department of Neurosciences, University of California San Diego, La Jolla, California, CA, United States of America
- Department of Pathology, University of California San Diego, La Jolla, California, CA, United States of America
| | - Wei Xiang
- Institute of Biochemistry, Emil-Fischer-Zentrum, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Jürgen Winkler
- Department of Molecular Neurology, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Beate Winner
- IZKF Junior Research Group III and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, FAU Erlangen-Nürnberg, Nikolaus-Fiebiger Center for Molecular Medicine, Erlangen, Germany
- * E-mail:
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Abstract
Adult neurogenesis is limited to specific brain regions in the mammalian brain, such as the hippocampal dentate gyrus and the subventricular zone/olfactory bulb system. Alterations in adult neurogenesis appear to be a common hallmark in different neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). This is remarkable, because the distinct pathological proteins responsible for the different diseases induce the loss of different neural populations. Impaired adult neurogenesis was shown in numerous animal models of neurodegenerative diseases; however, only few postmortem studies have been performed. We will review concepts related to the interplay between cellular plasticity in regions of adult neurogenesis with a specific focus on cell-autonomous and non-cell-autonomous factors. Furthermore, various strategies aimed to stimulate neuronal plasticity will be discussed within the context of a potential translation into therapeutic approaches for neuropsychiatric symptoms associated with PD, HD, and AD.
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Affiliation(s)
- Beate Winner
- IZKF Junior Research Group III, Interdisciplinary Center for Clinical Research, Nikolaus-Fiebiger Center for Molecular Medicine, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Jürgen Winkler
- Department of Molecular Neurology, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany
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Le Grand JN, Gonzalez-Cano L, Pavlou MA, Schwamborn JC. Neural stem cells in Parkinson's disease: a role for neurogenesis defects in onset and progression. Cell Mol Life Sci 2015; 72:773-97. [PMID: 25403878 PMCID: PMC11113294 DOI: 10.1007/s00018-014-1774-1] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 10/09/2014] [Accepted: 11/03/2014] [Indexed: 12/27/2022]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, non-motor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/β-catenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PD-related genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.
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Affiliation(s)
- Jaclyn Nicole Le Grand
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg
| | - Laura Gonzalez-Cano
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg
| | - Maria Angeliki Pavlou
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg
| | - Jens C. Schwamborn
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg
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Swaminathan A, Kumar M, Halder Sinha S, Schneider-Anthony A, Boutillier AL, Kundu TK. Modulation of neurogenesis by targeting epigenetic enzymes using small molecules: an overview. ACS Chem Neurosci 2014; 5:1164-77. [PMID: 25250644 DOI: 10.1021/cn500117a] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Neurogenesis consists of a plethora of complex cellular processes including neural stem cell (NSC) proliferation, migration, maturation or differentiation to neurons, and finally integration into the pre-existing neural circuits in the brain, which are temporally regulated and coordinated sequentially. Mammalian neurogenesis begins during embryonic development and continues in postnatal brain (adult neurogenesis). It is now evident that adult neurogenesis is driven by extracellular and intracellular signaling pathways, where epigenetic modifications like reversible histone acetylation, methylation, as well as DNA methylation play a vital role. Epigenetic regulation of gene expression during neural development is governed mainly by histone acetyltransferases (HATs), histone methyltransferase (HMTs), DNA methyltransferases (DNMTs), and also the enzymes for reversal, like histone deacetylases (HDACs), and many of these have also been shown to be involved in the regulation of adult neurogenesis. The contribution of these epigenetic marks to neurogenesis is increasingly being recognized, through knockout studies and small molecule modulator based studies. These small molecules are directly involved in regeneration and repair of neurons, and not only have applications from a therapeutic point of view, but also provide a tool to study the process of neurogenesis itself. In the present Review, we will focus on small molecules that act predominantly on epigenetic enzymes to enhance neurogenesis and neuroprotection and discuss the mechanism and recent advancements in their synthesis, targeting, and biology.
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Affiliation(s)
- Amrutha Swaminathan
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Manoj Kumar
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Sarmistha Halder Sinha
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Anne Schneider-Anthony
- Laboratoire de Neurosciences
Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS,
GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Anne-Laurence Boutillier
- Laboratoire de Neurosciences
Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS,
GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Tapas K Kundu
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
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Hippocampal proliferation is increased in presymptomatic Parkinson's disease and due to microglia. Neural Plast 2014; 2014:959154. [PMID: 25197578 PMCID: PMC4147270 DOI: 10.1155/2014/959154] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 07/01/2014] [Indexed: 01/08/2023] Open
Abstract
Besides dopamine-deficiency related motor symptoms, nonmotor symptoms, including cognitive changes occur in Parkinson's disease (PD) patients, that may relate to accumulation of α-synuclein in the hippocampus (HC). This brain region also contains stem cells that can proliferate. This is a well-regulated process that can, for example, be altered by neurodegenerative conditions. In contrast to proliferation in the substantia nigra and subventricular zone, little is known about the HC in PD. In addition, glial cells contribute to neurodegenerative processes and may proliferate in response to PD pathology. In the present study, we questioned whether microglial cells proliferate in the HC of established PD patients versus control subjects or incidental Lewy body disease (iLBD) cases as a prodromal state of PD. To this end, proliferation was assessed using the immunocytochemical marker minichromosome maintenance protein 2 (MCM2). Colocalization with Iba1 was performed to determine microglial proliferation. MCM2-positive cells were present in the HC of controls and were significantly increased in the presymptomatic iLBD cases, but not in established PD patients. Microglia represented the majority of the proliferating cells in the HC. This suggests an early microglial response to developing PD pathology in the HC and further indicates that neuroinflammatory processes play an important role in the development of PD pathology.
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Adult hippocampal neurogenesis in Parkinson's disease: impact on neuronal survival and plasticity. Neural Plast 2014; 2014:454696. [PMID: 25110593 PMCID: PMC4106176 DOI: 10.1155/2014/454696] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 06/19/2014] [Indexed: 12/23/2022] Open
Abstract
In Parkinson's disease (PD) and other synucleinopathies, chronic neurodegeneration occurs within different areas of the central nervous system leading to progressive motor and nonmotor symptoms. The symptomatic treatment options that are currently available do not slow or halt disease progression. This highlights the need of a better understanding of disease mechanisms and disease models. The generation of newborn neurons in the adult hippocampus and in the subventricular zone/olfactory bulb system is affected by many different regulators and possibly involved in memory processing, depression, and olfaction, symptoms which commonly occur in PD. The pathology of the adult neurogenic niches in human PD patients is still mostly elusive, but different preclinical models have shown profound alterations of adult neurogenesis. Alterations in stem cell proliferation, differentiation, and survival as well as neurite outgrowth and spine formation have been related to different aspects in PD pathogenesis. Therefore, neurogenesis in the adult brain provides an ideal model to study disease mechanisms and compounds. In addition, adult newborn neurons have been proposed as a source of endogenous repair. Herein, we review current knowledge about the adult neurogenic niches in PD and highlight areas of future research.
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Neuner J, Ovsepian SV, Dorostkar M, Filser S, Gupta A, Michalakis S, Biel M, Herms J. Pathological α-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb. Nat Commun 2014; 5:3915. [PMID: 24867427 PMCID: PMC4050256 DOI: 10.1038/ncomms4915] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 04/18/2014] [Indexed: 12/21/2022] Open
Abstract
Although the role of noxious α-synuclein (α-SYN) in the degeneration of midbrain dopaminergic
neurons and associated motor deficits of Parkinson’s disease is
recognized, its impact on non-motor brain circuits and related symptoms remains
elusive. Through combining in vivo two-photon imaging with time-coded
labelling of neurons in the olfactory bulb of A30P α-SYN transgenic mice, we show impaired growth and
branching of dendrites of adult-born granule cells (GCs), with reduced gain and
plasticity of dendritic spines. The spine impairments are especially pronounced
during the critical phase of integration of new neurons into existing circuits.
Functionally, retarded dendritic expansion translates into reduced electrical
capacitance with enhanced intrinsic excitability and responsiveness of GCs to
depolarizing inputs, while the spine loss correlates with decreased frequency of
AMPA-mediated miniature EPSCs.
Changes described here are expected to interfere with the functional integration and
survival of new GCs into bulbar networks, contributing towards olfactory deficits
and related behavioural impairments. Aggregation-prone forms of α-synuclein lead to
degeneration of midbrain dopaminergic neurons, as seen in Parkinson’s
disease, but less is known about the effects that the noxious protein has in other brain
regions. Here, the authors investigate the effect of a pathological form of
α-synuclein on the functional integration of new neurons into the olfactory
bulb of adult mice.
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Affiliation(s)
- Johanna Neuner
- Center for Neuropathology and Prion Research, Department for Translationsal Brain Research, Ludwig Maximilian University, Feodor-Lynen-Strassee 23, Munich 81377, Germany
| | - Saak V Ovsepian
- German Center for Neurodegeneratione Diseases (DZNE), Department for Translational Brain Research, Feodor-Lynen-Strasse 23, Munich 81377, Germany
| | - Mario Dorostkar
- Center for Neuropathology and Prion Research, Department for Translationsal Brain Research, Ludwig Maximilian University, Feodor-Lynen-Strassee 23, Munich 81377, Germany
| | - Severin Filser
- German Center for Neurodegeneratione Diseases (DZNE), Department for Translational Brain Research, Feodor-Lynen-Strasse 23, Munich 81377, Germany
| | - Aayush Gupta
- Center for Neuropathology and Prion Research, Department for Translationsal Brain Research, Ludwig Maximilian University, Feodor-Lynen-Strassee 23, Munich 81377, Germany
| | - Stylianos Michalakis
- Center for Integrated Protein Science Munich, (CiPSM) and Department of Pharmacy-Center for Drug Research, Ludwig Maximilian University, Butenandtstrasse 5-13, Munich 81377, Germany
| | - Martin Biel
- Center for Integrated Protein Science Munich, (CiPSM) and Department of Pharmacy-Center for Drug Research, Ludwig Maximilian University, Butenandtstrasse 5-13, Munich 81377, Germany
| | - Jochen Herms
- 1] German Center for Neurodegeneratione Diseases (DZNE), Department for Translational Brain Research, Feodor-Lynen-Strasse 23, Munich 81377, Germany [2] Munich Cluster of Systems Neurology (SyNergy), Ludwig Maximilian University, Feodor-Lynen-Strasse 23, Munich 81377, Germany
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Richter F, Gao F, Medvedeva V, Lee P, Bove N, Fleming SM, Michaud M, Lemesre V, Patassini S, De La Rosa K, Mulligan CK, Sioshansi PC, Zhu C, Coppola G, Bordet T, Pruss RM, Chesselet MF. Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons. Neurobiol Dis 2014; 69:263-75. [PMID: 24844147 DOI: 10.1016/j.nbd.2014.05.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 05/02/2014] [Accepted: 05/06/2014] [Indexed: 12/14/2022] Open
Abstract
Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson's disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4months of age, approximately 10months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.
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Affiliation(s)
- Franziska Richter
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Fuying Gao
- Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Vera Medvedeva
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Patrick Lee
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Nicholas Bove
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Sheila M Fleming
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Magali Michaud
- Trophos S.A. Parc Scientifique de Luminy, Case 931, 13288 Marseille Cedex 9, France
| | - Vincent Lemesre
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Stefano Patassini
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Krystal De La Rosa
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Caitlin K Mulligan
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Pedrom C Sioshansi
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Chunni Zhu
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Giovanni Coppola
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA; Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Thierry Bordet
- Trophos S.A. Parc Scientifique de Luminy, Case 931, 13288 Marseille Cedex 9, France
| | - Rebecca M Pruss
- Trophos S.A. Parc Scientifique de Luminy, Case 931, 13288 Marseille Cedex 9, France
| | - Marie-Françoise Chesselet
- Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA.
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Harnessing neurogenesis for the possible treatment of Parkinson's disease. J Comp Neurol 2014; 522:2817-30. [DOI: 10.1002/cne.23607] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 02/24/2014] [Accepted: 04/08/2014] [Indexed: 01/05/2023]
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