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1
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Samson JS, Rajagopal K, Parvathi VD. Outlook of SNCA (α-synuclein) transgenic fly models in delineating the sequel of mitochondrial dysfunction in Parkinson's disease. Brain Res 2025; 1852:149505. [PMID: 39954798 DOI: 10.1016/j.brainres.2025.149505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/21/2024] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with mechanisms that results in loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. Being a complex heterogeneous disorder, there is a requisite in discovering the underlying molecular signatures that could potentially help in resolving challenges associated with diagnosis as well as therapeutic management. SNCA gene that encodes for the protein α-synuclein is widely known for its indispensable role in aggravating the progression of sporadic and familial PD, upon mutations. Likewise, mitochondrial dysfunction is inferred to be playing a central role in both forms of PD. Observations from experimental models and human PD cases displayed strong evidence for disruption of mitochondrial dynamics, inhibition of mitochondrial complex I protein's function and elevation in reactive oxygen species (ROS) by the toxic aggregation of α-synuclein. Further, recent studies have raised the possibility of an underlying relationship, where the α-synuclein toxicity is exacerbated by the mutant mitochondrial complex proteins and vice-versa. In this review, we provide an overview of mechanisms influencing α-synuclein-related neurodegeneration, particularly, emphasizing the role of SNCA (α-synuclein) gene in leading to altered mitochondrial biogenesis during PD. We have described how transgenic Drosophila models were reliable at recapitulating some of the essential characteristics of PD. In addition, we highlight the capability of utilizing transgenic fly models in deciphering the altered α-synuclein toxicity and mitochondrial dysfunction, as induced by defects in the mitochondrial DNA.
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Affiliation(s)
- Jennifer Sally Samson
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India.
| | | | - Venkatachalam Deepa Parvathi
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India.
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2
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Vekrellis K, Emmanouilidou E, Xilouri M, Stefanis L. α-Synuclein in Parkinson's Disease: 12 Years Later. Cold Spring Harb Perspect Med 2024; 14:a041645. [PMID: 39349314 PMCID: PMC11529858 DOI: 10.1101/cshperspect.a041645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
Abstract
α-Synuclein (AS) is a small presynaptic protein that is genetically, biochemically, and neuropathologically linked to Parkinson's disease (PD) and related synucleinopathies. We present here a review of the topic of this relationship, focusing on more recent knowledge. In particular, we review the genetic evidence linking AS to familial and sporadic PD, including a number of recently identified point mutations in the SNCA gene. We briefly go over the relevant neuropathological findings, stressing the evidence indicating a correlation between aberrant AS deposition and nervous system dysfunction. We analyze the structural characteristics of the protein, in relation to both its physiologic and pathological conformations, with particular emphasis on posttranslational modifications, aggregation properties, and secreted forms. We review the interrelationship of AS with various cellular compartments and functions, with particular focus on the synapse and protein degradation systems. We finally go over the recent exciting data indicating that AS can provide the basis for novel robust biomarkers in the field of synucleinopathies, while at the same time results from the first clinical trials specifically targeting AS are being reported.
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Affiliation(s)
- Kostas Vekrellis
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
| | - Evangelia Emmanouilidou
- Laboratory of Biochemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens 15784, Greece
| | - Maria Xilouri
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
| | - Leonidas Stefanis
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, Athens 11528, Greece; and Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
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3
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Kamano S, Ozawa D, Ikenaka K, Nagai Y. Role of Lipids in the Pathogenesis of Parkinson's Disease. Int J Mol Sci 2024; 25:8935. [PMID: 39201619 PMCID: PMC11354291 DOI: 10.3390/ijms25168935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/07/2024] [Accepted: 08/10/2024] [Indexed: 09/02/2024] Open
Abstract
Aggregation of α-synuclein (αSyn) and its accumulation as Lewy bodies play a central role in the pathogenesis of Parkinson's disease (PD). However, the mechanism by which αSyn aggregates in the brain remains unclear. Biochemical studies have demonstrated that αSyn interacts with lipids, and these interactions affect the aggregation process of αSyn. Furthermore, genetic studies have identified mutations in lipid metabolism-associated genes such as glucocerebrosidase 1 (GBA1) and synaptojanin 1 (SYNJ1) in sporadic and familial forms of PD, respectively. In this review, we focus on the role of lipids in triggering αSyn aggregation in the pathogenesis of PD and propose the possibility of modulating the interaction of lipids with αSyn as a potential therapy for PD.
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Grants
- 24H00630 Ministry of Education, Culture, Sports, Science and Technology
- 21H02840 Ministry of Education, Culture, Sports, Science and Technology
- 17K19658 Ministry of Education, Culture, Sports, Science and Technology
- 20H05927 Ministry of Education, Culture, Sports, Science and Technology
- JP16ek0109018 Japan Agency for Medical Research and Development
- JP19ek0109222 Japan Agency for Medical Research and Development
- 30-3 National Center of Neurology and Psychiatry
- 30-9 National Center of Neurology and Psychiatry
- 3-9 National Center of Neurology and Psychiatry
- 6-9 National Center of Neurology and Psychiatry
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Affiliation(s)
- Shumpei Kamano
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan; (S.K.); (D.O.)
| | - Daisaku Ozawa
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan; (S.K.); (D.O.)
| | - Kensuke Ikenaka
- Department of Neurology, Osaka University Graduate School of Medicine, Suita 565-0871, Osaka, Japan;
| | - Yoshitaka Nagai
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan; (S.K.); (D.O.)
- Life Science Research Institute, Kindai University, Osaka-Sayama 589-8511, Osaka, Japan
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4
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Sun Z, Kantor B, Chiba-Falek O. Neuronal-type-specific epigenome editing to decrease SNCA expression: Implications for precision medicine in synucleinopathies. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102084. [PMID: 38130373 PMCID: PMC10732167 DOI: 10.1016/j.omtn.2023.102084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 11/22/2023] [Indexed: 12/23/2023]
Abstract
Overexpression of SNCA has been implicated in the pathogenesis of synucleinopathies, particularly Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While PD and DLB share some clinical and pathological similarities, each disease presents distinct characteristics, including the primary affected brain region and neuronal type. We aimed to develop neuronal-type-specific SNCA-targeted epigenome therapies for synucleinopathies. The system is based on an all-in-one lentiviral vector comprised of CRISPR-dSaCas9 and guide RNA (gRNA) targeted at SNCA intron 1 fused with a synthetic repressor molecule of Krüppel-associated box (KRAB)/ methyl CpG binding protein 2 (MeCp2) transcription repression domain (TRD). To achieve neuronal-type specificity for dopaminergic and cholinergic neurons, the system was driven by tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) promoters, respectively. Delivering the system into human induced pluripotent stem cell (hiPSC)-derived dopaminergic and cholinergic neurons from a patient with the SNCA triplication resulted in efficient and neuronal-type-specific downregulation of SNCA-mRNA and protein. Furthermore, the reduction in SNCA levels by the gRNA-dSaCas9-repressor system rescued disease-related cellular phenotypes including Ser129-phophorylated α-synuclein, neuronal viability, and mitochondrial dysfunction. We established a novel neuronal-type-specific SNCA-targeted epigenome therapy and provided in vitro proof of concept using human-based disease models. Our results support the therapeutic potential of our system for PD and DLB and provide the foundation for further preclinical studies in animal models toward investigational new drug (IND) enablement and clinical trials.
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Affiliation(s)
| | - Boris Kantor
- Viral Vector Core, Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Ornit Chiba-Falek
- Division of Translational Brain Sciences, Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA
- Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC 27710, USA
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5
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Ozoran H, Srinivasan R. Astrocytes and Alpha-Synuclein: Friend or Foe? JOURNAL OF PARKINSON'S DISEASE 2023; 13:1289-1301. [PMID: 38007674 PMCID: PMC10741342 DOI: 10.3233/jpd-230284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/21/2023] [Indexed: 11/27/2023]
Abstract
Despite its devastating disease burden and alarming prevalence, the etiology of Parkinson's disease (PD) remains to be completely elucidated. PD is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta and this correlates with the accumulation of misfolded α-synuclein. While the aggregation of α-synuclein in the form of Lewy bodies or Lewy neurites is a well-established intraneuronal hallmark of the disease process, our understanding of the glial contribution to aberrant α-synuclein proteostasis is lacking. In this regard, restoring astrocyte function during early PD could offer a promising therapeutic avenue and understanding the involvement of astrocytes in handling/mishandling of α-synuclein is of particular interest. Here, we explore the growing body of scientific literature implicating aberrant astrocytic α-synuclein proteostasis with the seemingly inexorable pathological sequelae typifying PD. We also provide a perspective on how heterogeneity in the morphological relationship between astrocytes and neurons will need to be considered in the context of PD pathogenesis.
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Affiliation(s)
- Hakan Ozoran
- Clinical Medical School, University of Oxford, Oxford, UK
- Green Templeton College, University of Oxford, Oxford, UK
| | - Rahul Srinivasan
- Department of Neuroscience & Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, TX, USA
- Texas A&M Institute for Neuroscience (TAMIN), College Station, TX, USA
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6
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Kilzheimer A, Hentrich T, Rotermund C, Kahle PJ, Schulze-Hentrich JM. Failure of diet-induced transcriptional adaptations in alpha-synuclein transgenic mice. Hum Mol Genet 2022; 32:450-461. [PMID: 36001352 PMCID: PMC9851747 DOI: 10.1093/hmg/ddac205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 08/03/2022] [Accepted: 08/17/2022] [Indexed: 01/24/2023] Open
Abstract
Nutritional influences have been discussed as potential modulators of Parkinson's disease (PD) pathology through various epidemiological and physiological studies. In animal models, a high-fat diet (HFD) with greater intake of lipid-derived calories leads to accelerated disease onset and progression. The underlying molecular mechanisms of HFD-induced aggravated pathology, however, remain largely unclear. In this study, we aimed to further illuminate the effects of a fat-enriched diet in PD by examining the brainstem and hippocampal transcriptome of alpha-synuclein transgenic mice exposed to a life-long HFD. Investigating individual transcript isoforms, differential gene expression and co-expression clusters, we observed that transcriptional differences between wild-type (WT) and transgenic animals intensified in both regions under HFD. Both brainstem and hippocampus displayed strikingly similar transcriptomic perturbation patterns. Interestingly, expression differences resulted mainly from responses in WT animals to HFD, while these genes remained largely unchanged or were even slightly oppositely regulated by diet in transgenic animals. Genes and co-expressed gene groups exhibiting this dysregulation were linked to metabolic and mitochondrial pathways. Our findings propose the failure of metabolic adaptions as the potential explanation for accelerated disease unfolding under exposure to HFD. From the identified clusters of co-expressed genes, several candidates lend themselves to further functional investigations.
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Affiliation(s)
| | | | - Carola Rotermund
- Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, 72074 Tübingen, Germany,German Center for Neurodegenerative Diseases (DZNE), 72074 Tübingen, Germany
| | - Philipp J Kahle
- Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, 72074 Tübingen, Germany
| | - Julia M Schulze-Hentrich
- To whom correspondence should be addressed at: Calwerstr. 7, 72076 Tübingen, Germany. Tel: +49-7071-2972276; Fax: +49-7071-29-5171;
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7
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Chedid J, Labrador-Garrido A, Zhong S, Gao J, Zhao Y, Perera G, Kim WS, Halliday GM, Dzamko N. A small molecule Toll-like receptor antagonist rescues α-synuclein fibril pathology. J Biol Chem 2022; 298:102260. [PMID: 35841928 PMCID: PMC9364105 DOI: 10.1016/j.jbc.2022.102260] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 11/27/2022] Open
Abstract
The propagation and accumulation of pathological α-synuclein protein is thought to underlie the clinical symptoms of the neurodegenerative movement disorder Parkinson's disease (PD). Consequently, there is significant interest in identifying the mechanisms that contribute to α-synuclein pathology, as these may inform therapeutic targets for the treatment of PD. One protein that appears to contribute to α-synuclein pathology is the innate immune pathogen recognition receptor, Toll-like receptor 2 (TLR). TLR2 is expressed on neurons and its activation results in the accumulation of α-synuclein protein; however, the precise mechanism by which TLR2 contributes to α-synuclein pathology is unclear. Herein we demonstrate using human cell models that neuronal TLR2 activation acutely impairs the autophagy lysosomal pathway and markedly potentiates α-synuclein pathology seeded with α-synuclein pre-formed fibrils (PFF). Moreover, α-synuclein pathology could be ameliorated with a novel small molecule TLR2 inhibitor, including in induced pluripotent stem cell-derived neurons from a patient with PD. These results provide further insight into how TLR2 activation may promote α-synuclein pathology in PD and support that TLR2 may be a potential therapeutic target for the treatment of PD.
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Affiliation(s)
- Jessica Chedid
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Adahir Labrador-Garrido
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Siying Zhong
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Jianqun Gao
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Ye Zhao
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Gayathri Perera
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Woojin S Kim
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Glenda M Halliday
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Nicolas Dzamko
- School of Medical Sciences, Faculty of Medicine and Health and the Brain and Mind Centre, University of Sydney, Camperdown, NSW, 2050, Australia.
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8
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Dutta D, Paidi RK, Raha S, Roy A, Chandra S, Pahan K. Treadmill exercise reduces α-synuclein spreading via PPARα. Cell Rep 2022; 40:111058. [PMID: 35830804 PMCID: PMC9308946 DOI: 10.1016/j.celrep.2022.111058] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 12/29/2021] [Accepted: 06/15/2022] [Indexed: 11/30/2022] Open
Abstract
This study underlines the importance of treadmill exercise in reducing α-synuclein (α-syn) spreading in the A53T brain and protecting nigral dopaminergic neurons. Preformed α-syn fibril (PFF) seeding in the internal capsule of young A53T α-syn mice leads to increased spreading of α-syn to substantia nigra and motor cortex and concomitant loss of nigral dopaminergic neurons. However, regular treadmill exercise decreases α-syn spreading in the brain and protects nigral dopaminergic neurons in PFF-seeded mice. Accordingly, treadmill exercise also mitigates α-synucleinopathy in aged A53T mice. While investigating this mechanism, we have observed that treadmill exercise induces the activation of peroxisome proliferator-activated receptor α (PPARα) in the brain to stimulate lysosomal biogenesis via TFEB. Accordingly, treadmill exercise remains unable to stimulate TFEB and reduce α-synucleinopathy in A53T mice lacking PPARα, and fenofibrate, a prototype PPARα agonist, reduces α-synucleinopathy. These results delineate a beneficial function of treadmill exercise in reducing α-syn spreading in the brain via PPARα.
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Affiliation(s)
- Debashis Dutta
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Ramesh Kumar Paidi
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Sumita Raha
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Avik Roy
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA
| | - Sujyoti Chandra
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Kalipada Pahan
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
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9
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Gene Co-expression Analysis of the Human Substantia Nigra Identifies ZNHIT1 as an SNCA Co-expressed Gene that Protects Against α-Synuclein-Induced Impairments in Neurite Growth and Mitochondrial Dysfunction in SH-SY5Y Cells. Mol Neurobiol 2022; 59:2745-2757. [PMID: 35175558 PMCID: PMC9016026 DOI: 10.1007/s12035-022-02768-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/03/2022] [Indexed: 11/17/2022]
Abstract
Parkinson’s disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.
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10
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Huang Y, Wei J, Cooper A, Morris MJ. Parkinson's Disease: From Genetics to Molecular Dysfunction and Targeted Therapeutic Approaches. Genes Dis 2022. [DOI: 10.1016/j.gendis.2021.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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11
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Suzuki M, Sango K, Nagai Y. Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson's Disease. Int J Mol Sci 2022; 23:ijms23031519. [PMID: 35163450 PMCID: PMC8835920 DOI: 10.3390/ijms23031519] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
α-Synuclein (αSyn) plays a major role in the pathogenesis of Parkinson’s disease (PD), which is the second most common neurodegenerative disease after Alzheimer’s disease. The accumulation of αSyn is a pathological hallmark of PD, and mutations in the SNCA gene encoding αSyn cause familial forms of PD. Moreover, the ectopic expression of αSyn has been demonstrated to mimic several key aspects of PD in experimental model systems. Among the various model systems, Drosophila melanogaster has several advantages for modeling human neurodegenerative diseases. Drosophila has a well-defined nervous system, and numerous tools have been established for its genetic analyses. The rapid generation cycle and short lifespan of Drosophila renders them suitable for high-throughput analyses. PD model flies expressing αSyn have contributed to our understanding of the roles of various disease-associated factors, including genetic and nongenetic factors, in the pathogenesis of PD. In this review, we summarize the molecular pathomechanisms revealed to date using αSyn-expressing Drosophila models of PD, and discuss the possibilities of using these models to demonstrate the biological significance of disease-associated factors.
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Affiliation(s)
- Mari Suzuki
- Diabetic Neuropathy Project, Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan;
- Department of Neurotherapeutics, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan
- Correspondence: (M.S.); (Y.N.); Tel.: +81-5316-3100 (M.S.); +81-72-366-0221 (Y.N.)
| | - Kazunori Sango
- Diabetic Neuropathy Project, Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan;
| | - Yoshitaka Nagai
- Department of Neurotherapeutics, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan
- Department of Neurology, Faculty of Medicine, Kindai University, Osaka-Sayama 589-8511, Japan
- Correspondence: (M.S.); (Y.N.); Tel.: +81-5316-3100 (M.S.); +81-72-366-0221 (Y.N.)
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12
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Eldeeb MA, Ragheb MA, Soliman MH, Fahlman RP. Regulation of Neurodegeneration-associated Protein Fragments by the N-degron Pathways. Neurotox Res 2022; 40:298-318. [PMID: 35043375 DOI: 10.1007/s12640-021-00396-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/20/2021] [Accepted: 07/20/2021] [Indexed: 12/20/2022]
Abstract
Among the most salient features that underpin the development of aging-related neurodegenerative disorders are the accumulation of protein aggregates and the decrease in cellular degradation capacity. Mammalian cells have evolved sophisticated quality control mechanisms to repair or eliminate the otherwise abnormal or misfolded proteins. Chaperones identify unstable or abnormal conformations in proteins and often help them regain their correct conformation. However, if repair is not an option, abnormal proteins are selectively degraded to prevent undesired interactions with other proteins or oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of abnormal or aberrant protein fragments. Despite an increasing understanding regarding the molecular responses that counteract the formation and clearance of dysfunctional protein aggregates, the role of N-degrons in these processes is poorly understood. Previous work demonstrated that the Arg-N-end rule degradation pathway (Arg-N-degron pathway) mediates the degradation of neurodegeneration-associated proteins, thereby regulating crucial signaling hubs that modulate the progression of neurodegenerative diseases. Herein, we discuss the functional interconnection between N-degron pathways and proteins associated with neurodegenerative disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. We also highlight some future prospects related to how the molecular insights gained from these processes will help unveil novel therapeutic approaches.
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Affiliation(s)
- Mohamed A Eldeeb
- Chemistry Department (Biochemistry Division), Faculty of Science, Cairo University, Giza, Egypt. .,Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
| | - Mohamed A Ragheb
- Chemistry Department (Biochemistry Division), Faculty of Science, Cairo University, Giza, Egypt
| | - Marwa H Soliman
- Chemistry Department (Biochemistry Division), Faculty of Science, Cairo University, Giza, Egypt
| | - Richard P Fahlman
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
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13
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Ojha AK, Rajasekaran R, Pandey AK, Dutta A, Seesala VS, Das SK, Chaudhury K, Dhara S. Nanotheranostics: Nanoparticles Applications, Perspectives, and Challenges. BIOSENSING, THERANOSTICS, AND MEDICAL DEVICES 2022:345-376. [DOI: 10.1007/978-981-16-2782-8_14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/19/2023]
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14
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Villanueva EB, Tresse E, Liu Y, Duarte JN, Jimenez-Duran G, Ejlerskov P, Kretz O, Loreth D, Goldmann T, Prinz M, Issazadeh-Navikas S. Neuronal TNFα, Not α-Syn, Underlies PDD-Like Disease Progression in IFNβ-KO Mice. Ann Neurol 2021; 90:789-807. [PMID: 34476836 DOI: 10.1002/ana.26209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 01/18/2023]
Abstract
OBJECTIVE Parkinson's disease (PD) manifests in motor dysfunction, non-motor symptoms, and eventual dementia (PDD). Neuropathological hallmarks include nigrostriatal neurodegeneration, Lewy body (LB) pathology, and neuroinflammation. Alpha-synuclein (α-syn), a primary component of LBs, is implicated in PD pathogenesis, accumulating, and aggregating in both familial and sporadic PD. However, as α-syn pathology is often comorbid with amyloid-beta (Aβ) plaques and phosphorylated tau (pTau) tangles in PDD, it is still unclear whether α-syn is the primary cause of neurodegeneration in sporadic PDD. We aimed to determine how the absence of α-syn would affect PDD manifestation. METHODS IFN-β knockout (Ifnb-/- ) mice spontaneously develop progressive behavior abnormalities and neuropathology resembling PDD, notably with α-syn+ LBs. We generated Ifnb/Snca double knockout (DKO) mice and evaluated their behavior and neuropathology compared with wild-type (Wt), Ifnb-/- , and Snca-/- mice using immunohistochemistry, electron microscopy, immunoblots, qPCR, and modification of neuronal signaling. RESULTS Ifnb/Snca DKO mice developed all clinical PDD-like behavioral manifestations induced by IFN-β loss. Independently of α-syn expression, lack of IFN-β alone induced Aβ plaques, pTau tangles, and LB-like Aβ+ /pTau+ inclusion bodies and neuroinflammation. IFN-β loss caused significant elevated glial and neuronal TNF-α and neuronal TNFR1, associated with neurodegeneration. Restoring neuronal IFN-β signaling or blocking TNFR1 rescued caspase 3/t-BID-mediated neuronal-death through upregulation of c-FLIPS and lowered intraneuronal Aβ and pTau accumulation. INTERPRETATION These findings increase our understanding of PD pathology and suggest that targeting α-syn alone is not sufficient to mitigate disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF-α/TNFR1 or IFN-β/IFNAR signaling, may attenuate disease. ANN NEUROL 2021;90:789-807.
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Affiliation(s)
- Erika B Villanueva
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Emilie Tresse
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Yawei Liu
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - João N Duarte
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Gisela Jimenez-Duran
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Patrick Ejlerskov
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Oliver Kretz
- Department of Internal Medicine III, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Desiree Loreth
- Institute of Cellular and Integrative Physiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias Goldmann
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiberg, Germany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiberg, Germany
| | - Shohreh Issazadeh-Navikas
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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15
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Oliveira LMA, Gasser T, Edwards R, Zweckstetter M, Melki R, Stefanis L, Lashuel HA, Sulzer D, Vekrellis K, Halliday GM, Tomlinson JJ, Schlossmacher M, Jensen PH, Schulze-Hentrich J, Riess O, Hirst WD, El-Agnaf O, Mollenhauer B, Lansbury P, Outeiro TF. Alpha-synuclein research: defining strategic moves in the battle against Parkinson's disease. NPJ Parkinsons Dis 2021; 7:65. [PMID: 34312398 PMCID: PMC8313662 DOI: 10.1038/s41531-021-00203-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 05/14/2021] [Indexed: 12/13/2022] Open
Abstract
With the advent of the genetic era in Parkinson's disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects >10 million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein's varied roles, as they are known today; and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD.
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Affiliation(s)
- Luis M A Oliveira
- The Michael J. Fox Foundation for Parkinson's Research, New York, NY, USA.
| | - Thomas Gasser
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - Robert Edwards
- Departments of Neurology and Physiology, UCSF School of Medicine, San Francisco, CA, USA
| | - Markus Zweckstetter
- German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
- Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Ronald Melki
- Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France
| | - Leonidas Stefanis
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- First Department of Neurology, Medical School of the National and Kapodistrian University of Athens, Athens, Greece
| | - Hilal A Lashuel
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Faculty of Life Sciences, EPFL, Lausanne, Switzerland
| | - David Sulzer
- Department of Psychiatry, Neurology, Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Kostas Vekrellis
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Glenda M Halliday
- University of Sydney, Brain and Mind Centre and Faculty of Medicine and Health, School of Medical Sciences, Sydney, NSW, Australia
| | - Julianna J Tomlinson
- Neuroscience Program, The Ottawa Hospital, Ottawa, ON, Canada
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
| | - Michael Schlossmacher
- Neuroscience Program, The Ottawa Hospital, Ottawa, ON, Canada
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
- Division of Neurology, The Ottawa Hospital, Ottawa, ON, Canada
| | - Poul Henning Jensen
- Aarhus University, Department of Biomedicine & DANDRITE, Danish Research Institute of Translational Neuroscience, Aarhus, Denmark
| | - Julia Schulze-Hentrich
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Olaf Riess
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Warren D Hirst
- Neurodegenerative Diseases Research Unit, Biogen, Cambridge, MA, USA
| | - Omar El-Agnaf
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Brit Mollenhauer
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
- Paracelsus-Elena-Klinik, Kassel, Germany
| | | | - Tiago F Outeiro
- German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.
- Max Planck Institute for Experimental Medicine, Göttingen, Germany.
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK.
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16
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Pedersen CC, Lange J, Førland MGG, Macleod AD, Alves G, Maple-Grødem J. A systematic review of associations between common SNCA variants and clinical heterogeneity in Parkinson's disease. NPJ PARKINSONS DISEASE 2021; 7:54. [PMID: 34210990 PMCID: PMC8249472 DOI: 10.1038/s41531-021-00196-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 06/02/2021] [Indexed: 11/09/2022]
Abstract
There is great heterogeneity in both the clinical presentation and rate of disease progression among patients with Parkinson’s disease (PD). This can pose prognostic difficulties in a clinical setting, and a greater understanding of the risk factors that contribute to modify disease course is of clear importance for optimizing patient care and clinical trial design. Genetic variants in SNCA are an established risk factor for PD and are candidates to modify disease presentation and progression. This systematic review aimed to summarize all available primary research reporting the association of SNCA polymorphisms with features of PD. We systematically searched PubMed and Web of Science, from inception to 1 June 2020, for studies evaluating the association of common SNCA variants with age at onset (AAO) or any clinical feature attributed to PD in patients with idiopathic PD. Fifty-eight studies were included in the review that investigated the association between SNCA polymorphisms and a broad range of outcomes, including motor and cognitive impairment, sleep disorders, mental health, hyposmia, or AAO. The most reproducible findings were with the REP1 polymorphism or rs356219 and an earlier AAO, but no clear associations were identified with an SNCA polymorphism and any individual clinical outcome. The results of this comprehensive summary suggest that, while there is evidence that genetic variance in the SNCA region may have a small impact on clinical outcomes in PD, the mechanisms underlying the association of SNCA polymorphisms with PD risk may not be a major factor driving clinical heterogeneity in PD.
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Affiliation(s)
- Camilla Christina Pedersen
- The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Johannes Lange
- The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | | | - Angus D Macleod
- Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
| | - Guido Alves
- The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.,Department of Neurology, Stavanger University Hospital, Stavanger, Norway
| | - Jodi Maple-Grødem
- The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway. .,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.
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17
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Gu J, Barrera J, Yun Y, Murphy SK, Beach TG, Woltjer RL, Serrano GE, Kantor B, Chiba-Falek O. Cell-Type Specific Changes in DNA Methylation of SNCA Intron 1 in Synucleinopathy Brains. Front Neurosci 2021; 15:652226. [PMID: 33994928 PMCID: PMC8113398 DOI: 10.3389/fnins.2021.652226] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/06/2021] [Indexed: 11/26/2022] Open
Abstract
Parkinson's disease (PD) and dementia with Lewy body (DLB) are the most common synucleinopathies. SNCA gene is a major genetic risk factor for these diseases group, and dysregulation of its expression has been implicated in the genetic etiologies of several synucleinopathies. DNA methylation at CpG island (CGI) within SNCA intron 1 has been suggested as a regulatory mechanism of SNCA expression, and changes in methylation levels at this region were associated with PD and DLB. However, the role of DNA methylation in the regulation of SNCA expression in a cell-type specific manner and its contribution to the pathogenesis of PD and DLB remain poorly understood, and the data are conflicting. Here, we employed a bisulfite pyrosequencing technique to profile the DNA methylation across SNCA intron 1 CGI in PD and DLB compared to age- and sex-matched normal control subjects. We analyzed homogenates of bulk post-mortem frozen frontal cortex samples and a subset of neuronal and glia nuclei sorted by the fluorescence-activated nuclei sorting (FANS) method. Bulk brain tissues showed no significant difference in the overall DNA methylation across SNCA intron 1 CGI region between the neuropathological groups. Sorted neuronal nuclei from PD frontal cortex showed significant lower levels of DNA methylation at this region compared to normal controls, but no differences between DLB and control, while sorted glia nuclei exhibited trends of decreased overall DNA methylation in DLB only. In conclusion, our data suggested disease-dependent cell-type specific differential DNA methylation within SNCA intron 1 CGI. These changes may affect SNCA dysregulation that presumably mediates disease-specific risk. Our results can be translated into the development of the SNCA intron 1 CGI region as an attractive therapeutics target for gene therapy in patients who suffer from synucleinopathies due to SNCA dysregulation.
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Affiliation(s)
- Jeffrey Gu
- Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, United States
- Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, United States
| | - Julio Barrera
- Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, United States
- Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, United States
| | - Young Yun
- Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, United States
- Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, United States
| | - Susan K. Murphy
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, United States
| | - Thomas G. Beach
- Banner Sun Health Research Institute, Sun City, AZ, United States
| | - Randy L. Woltjer
- Layton Aging and Alzheimer’s Disease Center, Department of Pathology, Oregon Health & Science University, Portland, OR, United States
| | - Geidy E. Serrano
- Banner Sun Health Research Institute, Sun City, AZ, United States
| | - Boris Kantor
- Viral Vector Core, Duke University Medical Center, Durham, NC, United States
- Department of Neurobiology, Duke University Medical Center, Durham, NC, United States
| | - Ornit Chiba-Falek
- Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, United States
- Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, United States
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18
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Soto-Rojas LO, Martínez-Dávila IA, Luna-Herrera C, Gutierrez-Castillo ME, Lopez-Salas FE, Gatica-Garcia B, Soto-Rodriguez G, Bringas Tobon ME, Flores G, Padilla-Viveros A, Bañuelos C, Blanco-Alvarez VM, Dávila-Ayala J, Reyes-Corona D, Garcés-Ramírez L, Hidalgo-Alegria O, De La Cruz-lópez F, Martinez-Fong D. Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat. Acta Neuropathol Commun 2020; 8:56. [PMID: 32321590 PMCID: PMC7178762 DOI: 10.1186/s40478-020-00933-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 04/14/2020] [Indexed: 02/05/2023] Open
Abstract
The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson’s disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of β-sitosterol β-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6 μg BSSG/μL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. We performed immunostainings against the pathological α-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker β-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using β-galactosidase (β-Gal) assay and active caspase-3 immunostaining, we assessed cell death mechanisms. Golgi-Cox staining was used to measure the density and types of dendritic spines of striatal medium spiny neurons. Motor and non-motor alterations were also evaluated. The study period comprised 15 to 120 days after the lesion. In the injured substantia nigra, BSSG caused a progressive α-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The α-synuclein immunoreactivity was also present within microglia cells. Decreased density of dopaminergic fibers and dendritic spines also occurred in the striatum. Remarkably, all the histopathological changes also appeared on the contralateral nigrostriatal system, and α-synuclein aggregates were present in other brain regions. Motor and non-motor behavioral alterations were progressive. Our data show that the stereotaxic BSSG administration reproduces PD α-synucleinopathy phenotype in the rat. This approach will aid in identifying the spread mechanism of α-synuclein pathology and validate anti-synucleinopathy therapies.
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19
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Bi M, Kang S, Du X, Jiao Q, Jiang H. Association between SNCA rs356220 polymorphism and Parkinson's disease: A meta-analysis. Neurosci Lett 2019; 717:134703. [PMID: 31863812 DOI: 10.1016/j.neulet.2019.134703] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/27/2019] [Accepted: 12/16/2019] [Indexed: 01/11/2023]
Abstract
Several studies have investigated the correlation between single nucleotide polymorphism (SNP) rs356220 in the α-synuclein (SNCA) gene and Parkinson's disease (PD) with inconsistent results. Herein, a meta-analysis was conducted to ascertain the association of the SNCA rs356220 polymorphism with the risk of PD. Six eligible articles involving 5333 PD cases and 5477 controls were included in this meta-analysis. The pooled odds ratios (OR) and 95 % confidence interval (CI) were calculated to estimate the association. The fixed or random effect was selected based on the homogeneity among studies. Heterogeneity was detected by I2. We performed sensitivity analysis to test the stablility of the results. Publication bias was evaluated by Funnel plot and Begg's test. The pooled results showed a significant association between SNCA rs356220 gene polymorphism and PD susceptibility in the codominant (FEM: OR = 1.31, 95 % CI = 1.24-1.39), dominant (FEM: OR = 1.38, 95 % CI = 1.27-1.49) and recessive (FEM: OR = 1.52, 95 % CI = 1.38-1.68) models. Furthermore, in the subgroup analysis stratified by ethnicity, increased risk of PD was identified in both Caucasian and Asian populations. Overall, the present meta-analysis provided evidence supporting that SNCA rs356220 polymorphism might act as a genetic susceptibility factor for PD.
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Affiliation(s)
- Mingxia Bi
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Shan Kang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China; Department of Laboratory, Qingdao Eighth People's Hospital, Qingdao, China
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
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20
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Kolber P, Krüger R. Gene-environment interaction and Mendelian randomisation. Rev Neurol (Paris) 2019; 175:597-603. [PMID: 31543362 DOI: 10.1016/j.neurol.2019.04.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 04/20/2019] [Indexed: 12/11/2022]
Abstract
Genetic factors only account for up to a third of the cases of Parkinson's disease (PD), while the remaining cases are of unknown aetiology. Environmental exposures (such as pesticides or heavy metals) and the interaction with genetic susceptibility factors (summarized in the concept of impaired xenobiotic metabolism) are believed to play a major role in the mechanisms of neurodegeneration. Beside of the classical association studies (e.g. genome-wide association studies), a novel approach to investigate environmental risk factors are Mendelian randomisation studies. This review explores the gene-environment interaction and the gain of Mendelian randomisation studies in assessing causalities of modifiable risk factors for PD.
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Affiliation(s)
- P Kolber
- Luxembourg Centre for Systems Biomedicine, Clinical and Experimental Neuroscience, University of Luxembourg, 4362 Belval, Esch-sur-Alzette, Luxembourg; Neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
| | - R Krüger
- Luxembourg Centre for Systems Biomedicine, Clinical and Experimental Neuroscience, University of Luxembourg, 4362 Belval, Esch-sur-Alzette, Luxembourg; Neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg; Luxembourg Institute of Health, Luxembourg, Luxembourg.
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21
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Hou B, Zhang X, Liu Z, Wang J, Xie A. Association of rs356219 and rs3822086 polymorphisms with the risk of Parkinson’s disease: A meta-analysis. Neurosci Lett 2019; 709:134380. [DOI: 10.1016/j.neulet.2019.134380] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/23/2019] [Accepted: 07/15/2019] [Indexed: 01/07/2023]
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Assessment of risk factor variants of LRRK2, MAPT, SNCA and TCEANC2 genes in Hungarian sporadic Parkinson's disease patients. Neurosci Lett 2019; 706:140-145. [PMID: 31085292 DOI: 10.1016/j.neulet.2019.05.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 05/09/2019] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Parkinson's disease is the second most common neurodegenerative disease. Lifestyle, environmental effects and several genetic factors have been proposed to contribute to its development. Though the majority of PD cases do not have a family history of disease, genetic alterations are proposed to be present in 60 percent of the more common sporadic cases. OBJECTIVE The aim of this study is to evaluate the frequency of PD related specific risk variants of LRRK2, MAPT, SNCA and PARK10 genes in the Hungarian population. Out of the ten investigated polymorphisms three are proposed to have protective effect and seven are putative risk factors. METHODS For genotyping, TaqMan allelic discrimination and restriction fragment length polymorphism method was used. LRRK2 mutations were investigated among 124 sporadic PD patients and 128 healthy controls. MAPT and SNCA variant frequencies were evaluated in a group of 123 patients and 122 controls, while PARK10 variant was studied in groups of 121 patients and 113 controls. RESULTS No significant difference could be detected in the frequencies of the investigated MAPT and PARK10 variants between the studied Hungarian PD cases and controls. The minor allele of the risk factor S1647T LRRK2 variant was found to be more frequent among healthy male individuals compared to patients. Moreover, in the frequency of one of the investigated SNCA variant a significant intergroup difference was detected. The minor allele (A) of rs356186 is proposed to be protective against developing the disease. In accord with data obtained in other populations, the AA genotype was significantly more frequent among Hungarian healthy controls compared to patients. Similarly, a significant difference in genotype distribution was also found in comparison of patients with late onset disease to healthy controls, which was due to the higher frequency of AG genotype among patients. CONCLUSION The frequencies of different gene variants show great differences in populations. Assessment of the frequency of variants of PD related genes variants is important in order to uncover the pathomechanisms underlying the disease, and to identify potential therapeutic targets. This is the first comprehensive study focusing on these genetic variants in the population of East-Central European region. Our results extend the knowledge on the world wide occurrence of these polymorphisms by demonstrating the occurrence of specific alleles and absence of others in Hungarian PD patients.
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SNCA rs11931074 polymorphism correlates with spontaneous brain activity and motor symptoms in Chinese patients with Parkinson's disease. J Neural Transm (Vienna) 2019; 126:1037-1045. [PMID: 31243602 DOI: 10.1007/s00702-019-02038-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/21/2019] [Indexed: 12/13/2022]
Abstract
The α-synuclein (SNCA) gene is thought to be involved in levels of α-synuclein and influence the susceptibility for the development of Parkinson's disease (PD). The aim of the present study is to explore the association among SNCA rs1193074 polymorphism, spontaneous brain activity and clinical symptoms in PD patients. 62 PD patients and 47 healthy controls (HC) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. Also blood sample of each participant was genotyped for rs11931074 polymorphism (PD: TT = 19, GT = 32, GG = 11; HC: TT = 10, GT = 25, GG = 12) and then examined to ascertain the influence of different genotypes on regional brain activity with amplitude low-frequency fluctuation analysis (ALFF). Furthermore, we evaluated the relationship among genotypes, interactive brain region and clinical symptoms in PD. Compared with HC subjects, PD patients showed decreased ALFF values in right lingual gyrus and increased ALFF values in right cerebellum posterior lobe. Significant interaction of ''groups × genotypes'' was found in the right angular gyrus, where there were higher ALFF values in TT genotype than in GT or GG genotype in the PD group and there was a contrary trend in the HC group. And further Spearman's correlative analyses revealed that ALFF values in right angular gyrus were negatively associated with unified Parkinson's disease rating scale (UPDRS) III score in PD-TT genotype. Our study shows for the first time that SNCA rs11931074 polymorphism might modulate brain functional alterations and correlate with motor symptoms in Chinese PD patients.
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Yang ZH, Li YS, Shi MM, Yang J, Liu YT, Mao CY, Fan Y, Hu XC, Shi CH, Xu YM. SNCA but not DNM3 and GAK modifies age at onset of LRRK2-related Parkinson's disease in Chinese population. J Neurol 2019; 266:1796-1800. [PMID: 31041581 DOI: 10.1007/s00415-019-09336-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/22/2019] [Accepted: 04/23/2019] [Indexed: 11/29/2022]
Abstract
BACKGROUND Recently, rs2421947 in DNM3 (dynamin 3) was reported as a genetic modifier of age at onset (AAO) of LRRK2 G2019S-related Parkinson's disease (PD) in a genome-wide association study in Arab-Berber population. Rs356219 in SNCA (α-synuclein) was also reported to regulate the AAO of LRRK2-related PD in European populations, and GAK (Cyclin G-associated kinase) rs1524282 was reported to be associated with an increased PD risk with an interaction with SNCA rs356219. G2019S variant is rare in Asian populations, whereas two other Asian-specific LRRK2 variants, G2385R and R1628P, are more frequent with a twofold increased risk of PD. METHODS In this study, we investigated whether rs2421947, rs356219 and rs1524282 modified AAO in LRRK2-related PD patients in Han Chinese population. We screened LRRK2 G2385R and R1628P variants in 732 PD patients and 1992 healthy controls, and genotyped DNM3 rs2421947, SNCA rs356219 and GAK rs1524282 among the LRRK2 carriers. RESULTS The SNCA rs356219-G allele was found to increase the risk of PD in LRRK2 carriers (OR 1.50, 95%CI 1.08-2.01, P = 0.016), and the AAO of AG + GG genotypes was 4 years earlier than AA genotype (P = 0.006). Nonetheless, no similar association was found in DNM3 rs2421947 and GAK rs1524282. CONCLUSIONS Our results show that SNCA but not DNM3 or GAK is associated with AAO of LRRK2-PD patients in Chinese population.
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Affiliation(s)
- Zhi-Hua Yang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China
| | - Yu-Sheng Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China
| | - Meng-Meng Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China
| | - Jing Yang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China
| | - Yu-Tao Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China
| | - Cheng-Yuan Mao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China
| | - Yu Fan
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China
| | - Xin-Chao Hu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China
| | - Chang-He Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China.
| | - Yu-Ming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China.
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25
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Monin M, Lesage S, Brice A. Basi molecolari della malattia di Parkinson. Neurologia 2019. [DOI: 10.1016/s1634-7072(18)41584-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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26
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SNCA variants and alpha-synuclein level in CD45+ blood cells in Parkinson’s disease. J Neurol Sci 2018; 395:135-140. [DOI: 10.1016/j.jns.2018.10.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 08/30/2018] [Accepted: 10/02/2018] [Indexed: 11/23/2022]
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Drosophila Models of Sporadic Parkinson's Disease. Int J Mol Sci 2018; 19:ijms19113343. [PMID: 30373150 PMCID: PMC6275057 DOI: 10.3390/ijms19113343] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/22/2018] [Accepted: 10/23/2018] [Indexed: 12/17/2022] Open
Abstract
Parkinson’s disease (PD) is the most common cause of movement disorders and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is increasingly recognized as a complex group of disorders presenting widely heterogeneous symptoms and pathology. With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress, aiming to provide mechanistic insights into the pathogenesis of PD. This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophilamelanogaster and discusses their methodologies, new findings, and future perspectives.
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Larsen SB, Hanss Z, Krüger R. The genetic architecture of mitochondrial dysfunction in Parkinson's disease. Cell Tissue Res 2018; 373:21-37. [PMID: 29372317 PMCID: PMC6015629 DOI: 10.1007/s00441-017-2768-8] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 12/07/2017] [Indexed: 12/17/2022]
Abstract
Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson's disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17-23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.
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Affiliation(s)
- S B Larsen
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Z Hanss
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
| | - R Krüger
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg City, Luxembourg
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O'Keeffe GW, Sullivan AM. Evidence for dopaminergic axonal degeneration as an early pathological process in Parkinson's disease. Parkinsonism Relat Disord 2018; 56:9-15. [PMID: 29934196 DOI: 10.1016/j.parkreldis.2018.06.025] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/21/2018] [Accepted: 06/17/2018] [Indexed: 12/21/2022]
Abstract
Parkinson's disease is a common neurodegenerative disorder presenting with a variety of motor and non-motor symptoms. The motor symptoms manifest as a result of the progressive degeneration of midbrain dopaminergic neurons. The axons of these neurons project to the striatum as the nigrostriatal pathway, which is a crucial part of the basal ganglia circuitry controlling movement. In addition to the neuronal degeneration, abnormal intraneuronal α-synuclein protein inclusions called Lewy bodies and Lewy neurites increase in number and spread throughout the nervous system as the disease progresses. While the loss of midbrain dopaminergic neurons is well-established as being central to motor symptoms, there is an increasing focus on the timing of nigrostriatal degeneration, with preclinical evidence suggesting that early axonal degeneration may play a key role in the early stages of Parkinson's disease. Here we review recent evidence for early midbrain dopaminergic axonal degeneration in patients with Parkinson's disease, and explore the potential role of α-synuclein accumulation in this process, with a focus on studies in human populations at the imaging, post-mortem, cellular and molecular levels. Finally, we discuss the implications of this for neurotrophic factor therapies for Parkinson's disease.
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Affiliation(s)
- Gerard W O'Keeffe
- Department of Anatomy and Neuroscience, Western Gateway Building, University College Cork, Cork, Ireland; Cork Neuroscience Centre, University College Cork, Cork, Ireland.
| | - Aideen M Sullivan
- Department of Anatomy and Neuroscience, Western Gateway Building, University College Cork, Cork, Ireland; Cork Neuroscience Centre, University College Cork, Cork, Ireland.
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30
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Piper DA, Sastre D, Schüle B. Advancing Stem Cell Models of Alpha-Synuclein Gene Regulation in Neurodegenerative Disease. Front Neurosci 2018; 12:199. [PMID: 29686602 PMCID: PMC5900030 DOI: 10.3389/fnins.2018.00199] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 03/13/2018] [Indexed: 12/15/2022] Open
Abstract
Alpha-synuclein (non A4 component of amyloid precursor, SNCA, NM_000345.3) plays a central role in the pathogenesis of Parkinson's disease (PD) and related Lewy body disorders such as Parkinson's disease dementia, Lewy body dementia, and multiple system atrophy. Since its discovery as a disease-causing gene in 1997, alpha-synuclein has been a central point of scientific interest both at the protein and gene level. Mutations, including copy number variants, missense mutations, short structural variants, and single nucleotide polymorphisms, can be causative for PD and affect conformational changes of the protein, can contribute to changes in expression of alpha-synuclein and its isoforms, and can influence regulation of temporal as well as spatial levels of alpha-synuclein in different tissues and cell types. A lot of progress has been made to understand both the physiological transcriptional and epigenetic regulation of the alpha-synuclein gene and whether changes in transcriptional regulation could lead to disease and neurodegeneration in PD and related alpha-synucleinopathies. Although the histopathological changes in these neurodegenerative disorders are similar, the temporal and spatial presentation and progression distinguishes them which could be in part due to changes or disruption of transcriptional regulation of alpha-synuclein. In this review, we describe different genetic alterations that contribute to PD and neurodegenerative conditions and review aspects of transcriptional regulation of the alpha-synuclein gene in the context of the development of PD. New technologies, advanced gene engineering and stem cell modeling, are on the horizon to shed further light on a better understanding of gene regulatory processes and exploit them for therapeutic developments.
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Affiliation(s)
- Desiree A Piper
- Parkinson's Institute and Clinical Center, Sunnyvale, CA, United States
| | - Danuta Sastre
- Parkinson's Institute and Clinical Center, Sunnyvale, CA, United States
| | - Birgitt Schüle
- Parkinson's Institute and Clinical Center, Sunnyvale, CA, United States
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31
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Suzuki M, Sango K, Wada K, Nagai Y. Pathological role of lipid interaction with α-synuclein in Parkinson's disease. Neurochem Int 2018; 119:97-106. [PMID: 29305919 DOI: 10.1016/j.neuint.2017.12.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 12/11/2017] [Accepted: 12/31/2017] [Indexed: 12/11/2022]
Abstract
Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In sporadic PD and DLB, normally harmless αSyn proteins without any mutations might gain toxic functions by unknown mechanisms. Thus, it is important to elucidate the factors promoting the toxic conversion of αSyn, towards understanding the pathogenesis of and developing disease-modifying therapies for PD and DLB. Accumulating biophysical and biochemical studies have demonstrated that αSyn interacts with lipid membrane, and the interaction influences αSyn oligomerization and aggregation. Furthermore, genetic and clinicopathological studies have revealed mutations in the glucocerebrosidase 1 (GBA1) gene, which encodes a degrading enzyme for the glycolipid glucosylceramide (GlcCer), as strong risk factors for PD and DLB, and we recently demonstrated that GlcCer promotes toxic conversion of αSyn. Moreover, pathological studies have shown the existence of αSyn pathology in lysosomal storage disorders (LSDs) patient' brain, in which glycosphingolipids (GSLs) is found to be accumulated. In this review, we focus on the lipids as a key factor for inducing wild-type (WT) αSyn toxic conversion, we summarize the knowledge about the interaction between αSyn and lipid membrane, and propose our hypothesis that aberrantly accumulated GSLs might contribute to the toxic conversion of αSyn. Identifying the trigger for toxic conversion of αSyn would open a new therapeutic road to attenuate or prevent crucial events leading to the formation of toxic αSyn.
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Affiliation(s)
- Mari Suzuki
- Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira 187-8502, Japan; Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, 156-8506, Japan.
| | - Kazunori Sango
- Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, 156-8506, Japan
| | - Keiji Wada
- Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira 187-8502, Japan
| | - Yoshitaka Nagai
- Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira 187-8502, Japan.
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32
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Fang J, Hou B, Liu H, Zhang X, Wang J, Zhou C, Xie A. Association between SNCA rs2736990 polymorphism and Parkinson's disease: a meta-analysis. Neurosci Lett 2017; 658:102-107. [PMID: 28844730 DOI: 10.1016/j.neulet.2017.08.051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 07/24/2017] [Accepted: 08/20/2017] [Indexed: 12/14/2022]
Abstract
Emerging evidence suggests that the SNP rs2736990 of SNCA is a susceptibility factor for idiopathic Parkinson's disease (PD) in different populations, but the studies which examined the association have provided inconsistent results. Therefore, we performed a meta-analysis of some case-control studies to obtain a more exact estimation of there associations. All the relevant studies were extracted from PubMed, Embase, EBSCO, Chineses national knowledge infrastructure, Google Scholar and Wanfang databases (up to February 2017). A total of six studies with 2525 PD cases and 2165 controls were eventually enrolled in the present meta-analysis based on the strict inclusion and exclusion criteria. The pooled analysis showed that there is a significant association between rs2736990 polymorphism and PD susceptibility in all genetic models (T vs. C: OR=0.772, 95%CI: 0.709-0.840, P=0.001; TT vs. CC: OR=0.586, 95%CI: 0.490-0.701, P=0.001; TC vs. CC: OR=0.814, 95%CI: 0.716-0.925, P=0.002; TT+TC vs. CC: OR=0.752, 95%CI: 0.666-0.848, P=0.001; TT vs. TC+CC: OR=0.658, 95%CI: 0.561-0.772, P=0.001). Our meta-analysis provides evidence that the T allele, TT and TC genotype of rs2736990(C/T) polymorphism may decrease the risk of PD.
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Affiliation(s)
- Jinni Fang
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Binghui Hou
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongxin Liu
- Department of Neurology, Yidu Central Hospital of Weifang, China
| | - Xiaona Zhang
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Wang
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chang Zhou
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Anmu Xie
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China.
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Glenn OC, Tagliafierro L, Beach TG, Woltjer RL, Chiba-Falek O. Interpreting Gene Expression Effects of Disease-Associated Variants: A Lesson from SNCA rs356168. Front Genet 2017; 8:133. [PMID: 28979294 PMCID: PMC5611418 DOI: 10.3389/fgene.2017.00133] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 09/07/2017] [Indexed: 11/13/2022] Open
Abstract
The SNCA intronic single nucleotide polymorphism (SNP), rs356168, has been associated with Parkinson's disease (PD) in large genome wide association studies (GWAS). Recently, the PD-risk allele, rs356168-G was shown to increase SNCA-mRNA expression using genome edited human induced pluripotent stem cells (iPSC)-derived neurons. In this study, as means of validation, we tested the effect of rs356168 on total SNCA-mRNA levels using brain tissues, temporal and frontal cortex, from healthy control donors. Carriers of the rs356168-G allele demonstrated a borderline significant decrease of SNCA-mRNA levels in temporal brain tissues (p = 0.02) compared to individuals homozygous for the 'A' allele. Similar trend, but weak, was observed in the analysis of frontal cortex samples, however, this analysis did not reach statistical significance. These results conflict with the recently reported effect of SNCA SNP rs356168 described above. Our study conveys the need to carefully interpret the precise molecular mechanism by which rs356168, or another tightly linked variant, affects the regulation of SNCA expression. The regulatory mechanisms that contribute to the observed associations between PD and the SNCA-3' linkage disequilibrium region warrant further investigations.
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Affiliation(s)
- Omolara-Chinue Glenn
- Department of Neurology, Duke University Medical Center, DurhamNC, United States.,Center for Genomic and Computational Biology, Duke University Medical Center, DurhamNC, United States
| | - Lidia Tagliafierro
- Department of Neurology, Duke University Medical Center, DurhamNC, United States.,Center for Genomic and Computational Biology, Duke University Medical Center, DurhamNC, United States
| | - Thomas G Beach
- Banner Sun Health Research Institute, Sun CityAZ, United States
| | - Randy L Woltjer
- Layton Aging and Alzheimer's Disease Center, Department of Pathology, Oregon Health and Science University, PortlandOR, United States
| | - Ornit Chiba-Falek
- Department of Neurology, Duke University Medical Center, DurhamNC, United States.,Center for Genomic and Computational Biology, Duke University Medical Center, DurhamNC, United States
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Genetic Variants in SNCA and the Risk of Sporadic Parkinson's Disease and Clinical Outcomes: A Review. PARKINSONS DISEASE 2017; 2017:4318416. [PMID: 28781905 PMCID: PMC5525082 DOI: 10.1155/2017/4318416] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 04/17/2017] [Accepted: 05/24/2017] [Indexed: 12/14/2022]
Abstract
There is increasing evidence of the contribution of genetic susceptibility to the etiology of Parkinson's disease (PD). Genetic variations in the SNCA gene are well established by linkage and genome-wide association studies. Positive associations of single nucleotide polymorphisms (SNPs) in SNCA and increased risk for PD were found. However, the role of SNCA variants in individual traits or phenotypes of PD is unknown. Here, we reviewed the current literature and identified 57 studies, performed in fourteen different countries, that investigated SNCA variants and susceptibility to PD. We discussed the findings based on environmental factors, history of PD, clinical outcomes, and ethnicity. In conclusion, SNPs within the SNCA gene can modify the susceptibility to PD, leading to increased or decreased risk. The risk associations of some SNPs varied among samples. Of notice, no studies in South American or African populations were found. There is little information about the effects of these variants on particular clinical aspects of PD, such as motor and nonmotor symptoms. Similarly, evidence of possible interactions between SNCA SNPs and environmental factors or disease progression is scarce. There is a need to expand the clinical applicability of these data as well as to investigate the role of SNCA SNPs in populations with different ethnic backgrounds.
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Campêlo CLC, Cagni FC, de Siqueira Figueredo D, Oliveira LG, Silva-Neto AB, Macêdo PT, Santos JR, Izídio GS, Ribeiro AM, de Andrade TG, de Oliveira Godeiro C, Silva RH. Variants in SNCA Gene Are Associated with Parkinson's Disease Risk and Cognitive Symptoms in a Brazilian Sample. Front Aging Neurosci 2017; 9:198. [PMID: 28676755 PMCID: PMC5476777 DOI: 10.3389/fnagi.2017.00198] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 06/02/2017] [Indexed: 02/06/2023] Open
Abstract
Genetic susceptibility contributes to the etiology of sporadic Parkinson's Disease (PD) and worldwide studies have found positive associations of polymorphisms in the alpha-synuclein gene (SNCA) with the risk for PD. However, little is known about the influence of variants of SNCA in individual traits or phenotypical aspects of PD. Further, there is a lack of studies with Latin-American samples. We evaluated the association between SNCA single nucleotide polymorphisms (single nucleotide polymorphisms, SNPs - rs2583988, rs356219, rs2736990, and rs11931074) and PD risk in a Brazilians sample. In addition, we investigated their potential interactions with environmental factors and specific clinical outcomes (motor and cognitive impairments, depression, and anxiety). A total of 105 PD patients and 101 controls participated in the study. Single locus analysis showed that the risk allele of all SNPs were more frequent in PD patients (p < 0.05), and the associations of SNPs rs2583988, rs356219, and rs2736990 with increased PD risk were confirmed. Further, the G-rs356219 and C-rs2736990 alleles were associated with early onset PD. T-rs2583988, G-rs356219 and C-2736990 alleles were significantly more frequent in PD patients with cognitive impairments than controls in this condition. In addition, in a logistic regression model, we found an association of cognitive impairment with PD, and the practice of cognitive activity and smoking habits had a protective effect. This study shows for the first time an association of SNCA polymorphism and PD in a South-American sample. In addition, we found an interaction between SNP rs356219 and a specific clinical outcome, i.e., the increased risk for cognitive impairment in PD patients.
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Affiliation(s)
- Clarissa L C Campêlo
- Memory Studies Laboratory, Physiology Department, Universidade Federal do Rio Grande do NorteNatal, Brazil
| | - Fernanda C Cagni
- Memory Studies Laboratory, Physiology Department, Universidade Federal do Rio Grande do NorteNatal, Brazil
| | | | - Luiz G Oliveira
- Medicine Department, Universidade Federal do Rio Grande do NorteNatal, Brazil
| | | | - Priscila T Macêdo
- Memory Studies Laboratory, Physiology Department, Universidade Federal do Rio Grande do NorteNatal, Brazil
| | - José R Santos
- Bioscience Department, Universidade Federal de SergipeItabaiana, Brazil
| | - Geison S Izídio
- Department of Cell Biology, Embryology and Genetics, Universidade Federal de Santa CatarinaFlorianópolis, Brazil
| | | | - Tiago G de Andrade
- Molecular Biology and Gene Expression Laboratory, Universidade Federal de AlagoasArapiraca, Brazil.,Faculty of Medicine, Universidade Federal de AlagoasMaceió, Brazil
| | | | - Regina H Silva
- Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São PauloSão Paulo, Brazil
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Deregulation of α-synuclein in Parkinson's disease: Insight from epigenetic structure and transcriptional regulation of SNCA. Prog Neurobiol 2017; 154:21-36. [PMID: 28445713 DOI: 10.1016/j.pneurobio.2017.04.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 04/18/2017] [Accepted: 04/19/2017] [Indexed: 01/19/2023]
Abstract
Understanding regulation of α-synuclein has long been a central focus for Parkinson's disease (PD) researchers. Accumulation of this protein in the Lewy body or neurites, mutations in the coding region of the gene and strong association of α-synuclein encoding gene multiplication (duplication/triplication) with familial form of PD have indicated the importance of this molecule in pathogenesis of the disease. Several years of research identified many potential faulty pathways associated with accumulation of α-synuclein inside dopaminergic neurons and its transmission to neighboring ones. Concurrently, an appreciable body of research is growing to understand the epigenetic and genetic deregulation of α-synuclein that might contribute to the disease pathology. Completion of the ENCODE (Encyclopedia of DNA Elements) project and recent advancement made in the epigenetic and trans factor mediated regulation of each gene, has tremendously accelerated the need to carefully understand the epigenetic structure of the gene (SNCA) encoding α-synuclein protein in order to decipher the regulation and contribution of α-synuclein to the pathogenesis of PD. We have also analyzed the detailed epigenetic structure of this gene with knowledge from ENCODE database, which may open new avenues in α-synuclein research. Interestingly, we have found that the gene contains several transcriptionally activate histone modifications and associated potential transcription factor binding sites in the non-coding areas that strongly suggest alternative regulatory pathways. Altogether this review will provide interesting insight of α-synuclein gene regulation from epigenetic, genetic and post-transcriptional perspectives and their potential implication in the PD pathogenesis.
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Tagliafierro L, Glenn OC, Zamora ME, Beach TG, Woltjer RL, Lutz MW, Chiba-Falek O. Genetic analysis of α-synuclein 3' untranslated region and its corresponding microRNAs in relation to Parkinson's disease compared to dementia with Lewy bodies. Alzheimers Dement 2017; 13:1237-1250. [PMID: 28431219 DOI: 10.1016/j.jalz.2017.03.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/08/2017] [Accepted: 03/09/2017] [Indexed: 11/29/2022]
Abstract
INTRODUCTION The α-synuclein (SNCA) gene has been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS A computational analysis of SNCA 3' untranslated region to identify potential microRNA (miRNA) binding sites and quantitative real-time polymerase chain reaction (PCR) to determine their expression in isogenic induced pluripotent stem cell-derived dopaminergic and cholinergic neurons as a model of PD and DLB, respectively, were performed. In addition, we performed a deep sequencing analysis of the SNCA 3' untranslated region of autopsy-confirmed cases of PD, DLB, and normal controls, followed by genetic association analysis of the identified variants. RESULTS We identified four miRNA binding sites and observed a neuronal-type-specific expression profile for each miRNA in the different isogenic induced pluripotent stem cell-derived dopaminergic and cholinergic neurons. Furthermore, we found that the short structural variant rs777296100-polyT was moderately associated with DLB but not with PD. DISCUSSION We suggest that the regulation of SNCA expression through miRNAs is neuronal-type-specific and possibly plays a part in the phenotypic heterogeneity of synucleinopathies. Furthermore, genetic variability in the SNCA gene may contribute to synucleinopathies in a pathology-specific manner.
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Affiliation(s)
- Lidia Tagliafierro
- Department of Neurology, Duke University Medical Center, Durham, North Carolina, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Omolara-Chinue Glenn
- Department of Neurology, Duke University Medical Center, Durham, North Carolina, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Madison E Zamora
- Department of Neurology, Duke University Medical Center, Durham, North Carolina, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Thomas G Beach
- Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Randy L Woltjer
- Department of Pathology, Layton Aging & Alzheimer's Disease Center, Oregon Health & Science University, Portland, Oregon, USA
| | - Michael W Lutz
- Department of Neurology, Duke University Medical Center, Durham, North Carolina, USA
| | - Ornit Chiba-Falek
- Department of Neurology, Duke University Medical Center, Durham, North Carolina, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, USA.
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Toffoli M, Dreussi E, Cecchin E, Valente M, Sanvilli N, Montico M, Gagno S, Garziera M, Polano M, Savarese M, Calandra-Buonaura G, Placidi F, Terzaghi M, Toffoli G, Gigli GL. SNCA 3′UTR genetic variants in patients with Parkinson’s disease and REM sleep behavior disorder. Neurol Sci 2017; 38:1233-1240. [DOI: 10.1007/s10072-017-2945-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 04/01/2017] [Indexed: 11/28/2022]
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Moustafa AA, Kéri S, Polner B, White C. Drift diffusion model of reward and punishment learning in rare alpha-synuclein gene carriers. J Neurogenet 2017; 31:17-22. [DOI: 10.1080/01677063.2017.1301939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Ahmed A. Moustafa
- School of Social Sciences and Psychology, Marcs Institute for Brain and Behaviour, Western Sydney University, Penrith, Australia
| | - Szabolcs Kéri
- Nyírő Gyula Hospital, National Institute of Psychiatry and Addictions, Budapest, Hungary
- Faculty of Medicine, Department of Physiology, University of Szeged, Szeged, Hungary
- Department of Cognitive Science, Budapest University of Technology and Economics, Budapest, Hungary
| | - Bertalan Polner
- Nyírő Gyula Hospital, National Institute of Psychiatry and Addictions, Budapest, Hungary
- Department of Cognitive Science, Budapest University of Technology and Economics, Budapest, Hungary
| | - Corey White
- Department of Psychology, Syracuse University, Syracuse, NY, USA
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40
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Structural variants in SNCA gene and the implication to synucleinopathies. Curr Opin Genet Dev 2017; 44:110-116. [PMID: 28319736 DOI: 10.1016/j.gde.2017.01.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 01/30/2017] [Indexed: 01/23/2023]
Abstract
Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed of aggregates of alpha-synuclein protein. Accumulating evidence, including genome-wide association studies, has implicated the alpha-synuclein (SNCA) gene in the etiology of synucleinopathies and it has been suggested that SNCA expression levels are critical for the development of these diseases. This review focuses on genetic variants from the class of structural variants (SVs), including multiplication of large genomic segments and short (<50bp) genomic variants such as simple sequence repeats (SSRs), within the SNCA locus. We provide evidence that SNCA-SVs play a key role in the pathogenesis of synucleinopathies via their effects on gene expression and on regulatory mechanisms including transcription and splicing.
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Huang J, Yang J, Shen Y, Jiang H, Han C, Zhang G, Liu L, Xu X, Li J, Lin Z, Xiong N, Zhang Z, Xiong J, Wang T. HMGB1 Mediates Autophagy Dysfunction via Perturbing Beclin1-Vps34 Complex in Dopaminergic Cell Model. Front Mol Neurosci 2017; 10:13. [PMID: 28197072 PMCID: PMC5281633 DOI: 10.3389/fnmol.2017.00013] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 01/09/2017] [Indexed: 12/14/2022] Open
Abstract
Parkinson’s disease (PD), a progressive neurodegenerative disorder, is characterized by irreversible dopaminergic neuron loss and intra-neuronal α-synuclein aggregation. High mobility group box 1 (HMGB1) has been proven to be involved in autophagy dysfunction induced by α-synuclein accumulation, and the Beclin1-vacuolar protein sorting 34 (Vps34) complex is of great importance to the initiation of autophagy. Nevertheless, the concrete interaction mechanism between HMGB1, α-synuclein and autophagy remains elusive, especially in the context of PD. Here in this study, we investigated the interaction between HMGB1 and α-synuclein in rotenone-induced PD cell models and their roles in autophagy flux. Results revealed elevated expression and cytosolic translocation of endogenous HMGB1 upon rotenone exposure. Besides, HMGB1 was found to be able to co-localize and interact with α-synuclein. Moreover, it had also been proven that HMGB1 could aggravate α-synuclein aggregation induced autophagy dysfunction via perturbing Beclin1-Vps34 complex formation. Based on these findings, we propose that HMGB1 is involved in rotenone-induced dopaminergic cell death via interacting with α-synuclein, perturbing the autophagy process, aggravating protein aggregation and finally propelling dopaminergic neurons to move from morbidity to mortality.
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Affiliation(s)
- Jinsha Huang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Jiaolong Yang
- Department of Neurology, Renmin Hospital, Hubei University of Medicine Shiyan, China
| | - Yan Shen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Haiyang Jiang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Chao Han
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Guoxin Zhang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Ling Liu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Xiaoyun Xu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Jie Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Zhicheng Lin
- Department of Psychiatry, Division of Alcohol and Drug Abuse, and Mailman Neuroscience Research Center, McLean Hospital, Harvard Medical School Belmont, MA, USA
| | - Nian Xiong
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Zhentao Zhang
- Department of Neurology, Renmin Hospital of Wuhan University Wuhan, China
| | - Jing Xiong
- Department of Neurology, Renmin Hospital of Wuhan University Wuhan, China
| | - Tao Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
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Wei Y, Yang N, Xu Q, Sun Q, Guo J, Li K, Liu Z, Yan X, Zhu X, Tang B. The rs3756063 polymorphism is associated with SNCA methylation in the Chinese Han population. J Neurol Sci 2016; 367:11-4. [DOI: 10.1016/j.jns.2016.05.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 05/04/2016] [Accepted: 05/18/2016] [Indexed: 11/24/2022]
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SNCA rs356182 variant increases risk of sporadic Parkinson's disease in ethnic Chinese. J Neurol Sci 2016; 368:231-4. [PMID: 27538639 DOI: 10.1016/j.jns.2016.07.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 06/24/2016] [Accepted: 07/12/2016] [Indexed: 02/05/2023]
Abstract
PURPOSE A genome-wide association study (GWAS) has recently identified a novel single nucleotide polymorphism (SNP) rs356182 at SNCA that can modulate the risk of Parkinson's disease (PD) in Caucasian ancestry. The present study was designed to clarify the strength of the association in ethnic Chinese population. METHODS Using a case-control methodology, we genotyped the SNP rs356182 to investigate the association with risk of PD. A total of 2205 ethnic Han Chinese study subjects comprising 1053 sporadic PD patients (581 males, 472 females) and 1152 controls (604 males, 548 females) were recruited from Mainland China. Additionally, the SHEsis software platform was applied for linkage disequilibrium (LD) analysis between rs356182 and another PD-associated synuclein SNP rs356219 we previously reported. RESULTS The frequency of SNCA rs356182-G allele was significantly higher in PD group than that in controls (odds ratio (OR)=1.470, 95% confidence interval (CI): 1.284-1.683, P=2.306E-8). Subjects carrying GG/AG genotype had an increased risk compared with the AA carriers (OR=1.162, 95% CI: 1.143-2.274, P=0.006). Among all the genotypes of rs356182, GG genotype showed the strongest association with risk of PD (GG vs. AG/AA, OR=1.620, 95% CI: 1.368-1.919, P=2.001E-8). However, the gender, onset age, disease duration, Hoehn-Yahr stage, UPDRS scores and other clinical features were similar between GG genotype carriers and non-carriers. No LD between rs356182 and rs356219 was found in our population (r(2)=0.016 and D'=0.163). CONCLUSION Our study firstly demonstrates that SNCA rs356182 variant has an increased risk of susceptibility to PD in Han Chinese population. Further functional analysis is required to determine the role of this SNP in development of PD.
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Tagliafierro L, Chiba-Falek O. Up-regulation of SNCA gene expression: implications to synucleinopathies. Neurogenetics 2016; 17:145-57. [PMID: 26948950 DOI: 10.1007/s10048-016-0478-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 02/27/2016] [Indexed: 01/06/2023]
Abstract
Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein (SNCA) gene in the etiology of synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic forms of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other synucleinopathies and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here, we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA down-regulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis-genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glial lineages involved in synucleinopathies representing an attractive strategy to elucidate-common and specific-SNCA-genetic variants, regulatory mechanisms, and vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for synucleinopathies.
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Affiliation(s)
- L Tagliafierro
- Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
| | - O Chiba-Falek
- Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA.
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45
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Association of Parkinson’s Disease GWAS-Linked Loci with Alzheimer’s Disease in Han Chinese. Mol Neurobiol 2016; 54:308-318. [DOI: 10.1007/s12035-015-9649-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 12/17/2015] [Indexed: 01/03/2023]
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46
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Ghanbari M, Darweesh SK, de Looper HW, van Luijn MM, Hofman A, Ikram MA, Franco OH, Erkeland SJ, Dehghan A. Genetic Variants in MicroRNAs and Their Binding Sites Are Associated with the Risk of Parkinson Disease. Hum Mutat 2015; 37:292-300. [DOI: 10.1002/humu.22943] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 12/04/2015] [Indexed: 12/21/2022]
Affiliation(s)
- Mohsen Ghanbari
- Department of Epidemiology; Erasmus University Medical Center; Rotterdam 3000 CA The Netherlands
- Department of Genetics, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Sirwan K.L. Darweesh
- Department of Epidemiology; Erasmus University Medical Center; Rotterdam 3000 CA The Netherlands
| | - Hans W.J. de Looper
- Department of Hematology, Erasmus University Medical Center; Cancer Institute; Rotterdam 3000 CA The Netherlands
| | - Marvin M. van Luijn
- Department of Immunology, MS Center ErasMS; Erasmus University Medical Center; Rotterdam 3000 CA The Netherlands
| | - Albert Hofman
- Department of Epidemiology; Erasmus University Medical Center; Rotterdam 3000 CA The Netherlands
- Department of Epidemiology; Harvard T.H. Chan School of Public Health; Boston Mass USA
| | - M. Arfan Ikram
- Department of Epidemiology; Erasmus University Medical Center; Rotterdam 3000 CA The Netherlands
| | - Oscar H. Franco
- Department of Epidemiology; Erasmus University Medical Center; Rotterdam 3000 CA The Netherlands
| | - Stefan J. Erkeland
- Department of Immunology; Erasmus University Medical Center; Rotterdam 3000 CA The Netherlands
| | - Abbas Dehghan
- Department of Epidemiology; Erasmus University Medical Center; Rotterdam 3000 CA The Netherlands
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Jian CD, Huang JM, Meng LQ, Li XB, Huang RY, Shi SL, Wu Y, Qin C, Chen J, Zhang YM, Wang S, Feng YL, Zhou SN. SNCA rs3822086 C>T Polymorphism Increases the Susceptibility to Parkinson's Disease in a Chinese Han Population. Genet Test Mol Biomarkers 2015. [PMID: 26203864 DOI: 10.1089/gtmb.2015.0046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Chong-Dong Jian
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jian-Min Huang
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Lan-Qing Meng
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Xue-Bin Li
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Rui-Ya Huang
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Sheng-Liang Shi
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuan Wu
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chao Qin
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jin Chen
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yan-Mei Zhang
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shuang Wang
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yin-Ling Feng
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Sheng-Nian Zhou
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Genetic Variants of SNCA Are Associated with Susceptibility to Parkinson's Disease but Not Amyotrophic Lateral Sclerosis or Multiple System Atrophy in a Chinese Population. PLoS One 2015. [PMID: 26208350 PMCID: PMC4514852 DOI: 10.1371/journal.pone.0133776] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background The polymorphisms of α-synuclein (SNCA), rs3775444, rs3822086 and rs11931074 that are strongly associated with Parkinson’s disease (PD) in Caucasian populations, were examined in this study to elucidate the role of polymorphisms in different ethnic backgrounds. The possible associations of these three polymorphisms were also investigated in PD, amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA) in a Chinese population based on the overlapping of clinical manifestations and pathological characteristics of these three neurodegenerative diseases. Methods A total of 1276 PD, 885 sporadic ALS (SALS), 364 MSA patients, and 846 healthy controls (HCs) were included. All subjects were genotyped for the three polymorphisms using Sequenom iPLEX Assay technology. Results Significant differences in the genotype distributions (p = 5.99E-06 and p = 4.98E-06, respectively) and the minor allele frequency (MAF) (p = 2.16E-06 and p = 2.15E-06, respectively) of SNCA rs3822086 (C) and rs11931074 (G) were observed between PD and HCs. However, no differences were found in the genotype distributions and MAF of SNCA rs3775444 (T) between PD and HCs. Haplotype that incorporated the three SNPs further strengthened the association with PD (best haplotype, p = 9.62E-005). No significant differences in the genotype distributions and MAF of the SNPs were found between SALS and HCs, MSA and HCs, and subgroups of PD and SALS. However, the MAF of SNCA rs3775444 (T) was significantly higher in MSA patients with frontal lobe dysfunction than MSA patients without dysfunction (p = 0.0002, OR 2.53, 95%CI: 1.55-4.15). Conclusion Our results suggest that the rs3822086 (C) allele and rs11931074 (G) allele in SNCA decrease the risk for PD, and SNCA rs11931074 may affect frontal lobe dysfunction of MSA in the Chinese population. However, these SNCA polymorphisms are not likely a common cause of SALS or MSA.
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A cytosine-thymine (CT)-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression. Alzheimers Dement 2015; 11:1133-43. [PMID: 26079410 DOI: 10.1016/j.jalz.2015.05.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 03/30/2015] [Accepted: 05/09/2015] [Indexed: 01/07/2023]
Abstract
INTRODUCTION We recently showed that tagging single-nucleotide polymorphisms across the SNCA locus were significantly associated with increased risk for Lewy body (LB) pathology in Alzheimer's disease (AD) cases. However, the actual genetic variant(s) that underlie the observed associations remain elusive. METHODS We used a bioinformatics algorithm to catalog structural variants in a region of SNCA intron 4, followed by phased sequencing. We performed a genetic association analysis in autopsy series of LB variant of Alzheimer's disease (LBV/AD) cases compared with AD-only controls. We investigated the biological functions by expression analysis using temporal-cortex samples. RESULTS We identified four distinct haplotypes within a highly polymorphic low-complexity cytosine-thymine (CT)-rich region. We showed that a specific haplotype conferred risk to develop LBV/AD. We demonstrated that the CT-rich site acts as an enhancer element, where the risk haplotype was significantly associated with elevated levels of SNCA messenger RNA. DISCUSSION We have discovered a novel haplotype in a CT-rich region in SNCA that contributes to LB pathology in AD patients, possibly via cis-regulation of the gene expression.
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50
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Transcriptional regulation of the α-synuclein gene in human brain tissue. Neurosci Lett 2015; 599:140-5. [PMID: 26002080 DOI: 10.1016/j.neulet.2015.05.029] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 05/14/2015] [Accepted: 05/15/2015] [Indexed: 12/15/2022]
Abstract
The transcriptional regulation of the gene encoding α-synuclein (SNCA) is thought to play a critical role in the pathogenesis of Parkinson's disease (PD), as common genetic variability in this gene is associated with an elevated risk of developing PD. However, the relevant mechanisms are still poorly understood. So far, only few proteins have been identified as transcription factors (TFs) of SNCA in cellular models. Here we show that two of these TFs bind to the DNA in human brain tissue: the zinc finger protein ZSCAN21 occupies a region within SNCA intron 1, as described before, while GATA2 occupies a specific region within intron 2, where we have identified a new binding site within the complex structure of the 5'-promoter region of SNCA. Electrophoretic mobility shift assays confirmed these binding sites. Genetic investigations revealed no polymorphisms or mutations within these sites. A better understanding of TF-DNA interactions within SNCA may allow to develop novel therapies designed to reduce α-synuclein levels.
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