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Fischer AL, Schmitz M, Thom T, Zafar S, Younas N, da Silva Correia S, da Silva Correia A, Eyyuboglu SC, Zerr I. Alpha-Synuclein Demonstrates Varying Binding Affinities With Different Tau Isoforms. J Neurochem 2025; 169:e70053. [PMID: 40165586 DOI: 10.1111/jnc.70053] [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: 08/16/2024] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
The hallmark of various neurodegenerative diseases is the accumulation and aggregation of amyloidogenic proteins, such as amyloid-beta (Aβ) and tau in Alzheimer's disease (AD) and alpha-synuclein (aSyn) in synucleinopathies. Many neurodegenerative diseases express mixed pathology. For instance, Lewy bodies are reported in tauopathies and neurofibrillary tau-tangles are detected in synucleinopathies, suggesting a potential co-existence or crosstalk of misfolded aSyn and tau. In the present study, we investigated the binding characteristics of monomeric aSyn with different tau isoforms by using surface plasmon resonance (SPR) spectroscopy allowing monitoring direct protein-protein interactions and their potential co-localization using SH-SY5Y cells. The calculation of the binding parameters (association and dissociation rate constants) indicated the strongest binding affinity between aSyn and tau isoform 1N3R followed by tau 2N3R and tau 2N4R. Co-localization studies in SH-SY5Y cells, treated with aSyn and all six tau isoforms revealed an intracellular co-localization of aSyn with different isoforms of tau. Subcellular fractionation confirmed the cellular uptake and colocalization of tau and aSyn in the same compartment, showing their expression in membrane, nuclear, and cytoskeletal fractions. Understanding the intricate interplay between aSyn and tau is crucial for unraveling the pathophysiology of PD, AD, and related neurodegenerative disorders, ultimately paving the way for the development of effective treatments targeting this interaction. In conclusion, our data indicate that aSyn and tau are direct interaction partners with varying binding affinities depending on the tau isoform. This interaction may be significant for understanding the pathophysiology of dementia with mixed pathologies.
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Affiliation(s)
- Anna-Lisa Fischer
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Matthias Schmitz
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Tobias Thom
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Saima Zafar
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Neelam Younas
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Susana da Silva Correia
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Angela da Silva Correia
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Sezgi Canaslan Eyyuboglu
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Inga Zerr
- Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
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Alpha-Synuclein and Cognitive Decline in Parkinson Disease. Life (Basel) 2021; 11:life11111239. [PMID: 34833115 PMCID: PMC8625417 DOI: 10.3390/life11111239] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/08/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022] Open
Abstract
Parkinson disease (PD) is the second most common neurodegenerative disorder in elderly people. It is characterized by the aggregation of misfolded alpha-synuclein throughout the nervous system. Aside from cardinal motor symptoms, cognitive impairment is one of the most disabling non-motor symptoms that occurs during the progression of the disease. The accumulation and spreading of alpha-synuclein pathology from the brainstem to limbic and neocortical structures is correlated with emerging cognitive decline in PD. This review summarizes the genetic and pathophysiologic relationship between alpha-synuclein and cognitive impairment in PD, together with potential areas of biomarker advancement.
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Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the APOE and MAPT Haplotypes. Genes (Basel) 2021; 12:genes12030423. [PMID: 33804213 PMCID: PMC7999745 DOI: 10.3390/genes12030423] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/01/2021] [Accepted: 03/10/2021] [Indexed: 12/17/2022] Open
Abstract
Genetic variations at the Apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) loci have been implicated in multiple neurogenerative diseases, but their exact molecular mechanisms are unclear. In this study, we performed transcript level linear modelling using the blood whole transcriptome data and genotypes of the 570 subjects in the Parkinson’s Progression Markers Initiative (PPMI) cohort. ApoE, MAPT haplotypes and two SNPs at the SNCA locus (rs356181, rs3910105) were used to detect expression quantitative trait loci eQTLs associated with the transcriptome and differential usage of transcript isoforms. As a result, we identified 151 genes associated with the genotypic variations, 29 cis and 122 trans eQTL positions. Profound effect with genome-wide significance of ApoE e4 haplotype on the expression of TOMM40 transcripts was identified. This finding potentially explains in part the frequently established genetic association with the APOE e4 haplotypes in neurodegenerative diseases. Moreover, MAPT haplotypes had significant differential impact on 23 transcripts from the 17q21.31 and 17q24.1 loci. MAPT haplotypes had also the largest up-regulating (256) and the largest down-regulating (−178) effect sizes measured as β values on two different transcripts from the same gene (LRRC37A2). Intronic SNP in the SNCA gene, rs3910105, differentially induced expression of three SNCA isoforms. In conclusion, this study established clear association between well-known haplotypic variance and transcript specific regulation in the blood. APOE e4 and MAPT H1/H2 haplotypic variants are associated with the expression of several genes related to the neurodegeneration.
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Feng ST, Wang ZZ, Yuan YH, Sun HM, Chen NH, Zhang Y. Update on the association between alpha-synuclein and tau with mitochondrial dysfunction: Implications for Parkinson's disease. Eur J Neurosci 2020; 53:2946-2959. [PMID: 32031280 DOI: 10.1111/ejn.14699] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 01/13/2020] [Accepted: 01/23/2020] [Indexed: 12/26/2022]
Abstract
The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing.
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Affiliation(s)
- Si-Tong Feng
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zhen-Zhen Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu-He Yuan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong-Mei Sun
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Nai-Hong Chen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Zhang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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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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Interactions Between α-Synuclein and Tau Protein: Implications to Neurodegenerative Disorders. J Mol Neurosci 2016; 60:298-304. [DOI: 10.1007/s12031-016-0829-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 08/30/2016] [Indexed: 01/28/2023]
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Shi C, Zheng Z, Wang Q, Wang C, Zhang D, Zhang M, Chan P, Wang X. Exploring the Effects of Genetic Variants on Clinical Profiles of Parkinson's Disease Assessed by the Unified Parkinson's Disease Rating Scale and the Hoehn-Yahr Stage. PLoS One 2016; 11:e0155758. [PMID: 27299523 PMCID: PMC4907455 DOI: 10.1371/journal.pone.0155758] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 05/04/2016] [Indexed: 11/25/2022] Open
Abstract
Many genetic variants have been linked to familial or sporadic Parkinson’s disease (PD), among which those identified in PARK16, BST1, SNCA, LRRK2, GBA and MAPT genes have been demonstrated to be the most common risk factors worldwide. Moreover, complex gene-gene and gene-environment interactions have been highlighted in PD pathogenesis. Compared to studies focusing on the predisposing effects of genes, there is a relative lack of research investigating how these genes and their interactions influence the clinical profiles of PD. In a cohort consisting of 2,011 Chinese Han PD patients, we selected 9 representative variants from the 6 above-mentioned common PD genes to analyze their main and epistatic effects on the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H-Y) stage of PD. With multiple linear regression models adjusting for medication status, disease duration, gender and age at onset, none of the variants displayed significant main effects on UPDRS or the H-Y scores. However, for gene-gene interaction analyses, 7 out of 37 pairs of variants showed significant or marginally significant associations with these scores. Among these, the GBA rs421016 (L444P)×LRRK2 rs33949390 (R1628P) interaction was consistently significant in relation to UPDRS III and UPDRS total (I+II+III), even after controlling for the family-wise error rate using False Discovery Rate (FDR-corrected p values are 0.0481 and 0.0070, respectively). Although the effects of the remaining pairs of variants did not survive the FDR correction, they showed marginally significant associations with either UPDRS or the H-Y stage (raw p<0.05). Our results highlight the importance of epistatic effects of multiple genes on the determination of PD clinical profiles and may have implications for molecular classification and personalized intervention of the disease.
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Affiliation(s)
- Chen Shi
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- Bioinformatics Center, School of Biomedical Engineering, Capital Medical University, Beijing, China
| | - Zheng Zheng
- Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Qi Wang
- Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America
| | - Chaodong Wang
- Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China
- Department of Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China
- Department of Neurology, The Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China
| | - Dabao Zhang
- Bioinformatics Center, School of Biomedical Engineering, Capital Medical University, Beijing, China
- Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America
| | - Min Zhang
- Bioinformatics Center, School of Biomedical Engineering, Capital Medical University, Beijing, China
- Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America
- Alzheimer Disease Center of Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
- * E-mail: (MZ); (PC); (XMW)
| | - Piu Chan
- Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China
- Department of Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China
- Key Laboratory on Neurodegenerative Disease of Ministry of Education and Key Laboratory on Parkinson’s Disease of Beijing, Beijing, China
- Parkinson Disease Center of Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
- * E-mail: (MZ); (PC); (XMW)
| | - Xiaomin Wang
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- Parkinson Disease Center of Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
- * E-mail: (MZ); (PC); (XMW)
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Yu WJ, Cheng L, Li NN, Wang L, Tan EK, Peng R. Interaction between SNCA, LRRK2 and GAK increases susceptibility to Parkinson's disease in a Chinese population. eNeurologicalSci 2015; 1:3-6. [PMID: 29479569 PMCID: PMC5852682 DOI: 10.1016/j.ensci.2015.08.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 08/03/2015] [Indexed: 02/05/2023] Open
Abstract
PD is a complex disease, and may result from gene–gene and gene–environment interactions. There are limited studies on gene–gene interactions in PD. We and others have previously shown that SNCA rs356219, LRRK2 (rs2046932 and rs7304279) and GAK (rs1564282) are risk factors in sporadic PD. Since the expression of SNCA and neurotoxicity of alpha-synuclein are affected by LRRK2 and GAK, we hypothesize that their genetic risk variants may interact with each other. Here we investigated the interaction of SNCA rs356219, LRRK2rs7304279 and rs2046932 and GAK rs1564282 using the Multifactor Dimensionality Reduction (MDR) in a Chinese PD patient–control series (534 patients and 435 controls) and the cumulative risk effect of SNCA, LRRK2 and GAK. The MDR analysis showed a significant gene–gene interaction between the rs356219 of SNCA, rs2046932 of LRRK2 and rs1564282 of GAK. Moreover, individuals with increasing numbers of variants had an increasing likelihood of having PD, compared with those carrying none of the variants. The estimated OR for developing PD in individuals carrying 3 variants was 5.89. We demonstrated for the first time that SNPs in SNCA, LRRK2 and GAK interacted with each other to confer an increased risk of PD. In addition, PD risk increased cumulatively with the increasing number of variants.
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Affiliation(s)
- Wen-Juan Yu
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Lan Cheng
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Nan-Nan Li
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Ling Wang
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Eng-King Tan
- Duke-NUS Graduate Medical School, Singapore, Singapore.,Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Singapore, Singapore
| | - Rong Peng
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China
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Alpha-synuclein and tau: teammates in neurodegeneration? Mol Neurodegener 2014; 9:43. [PMID: 25352339 PMCID: PMC4230508 DOI: 10.1186/1750-1326-9-43] [Citation(s) in RCA: 195] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 10/16/2014] [Indexed: 11/25/2022] Open
Abstract
The accumulation of α-synuclein aggregates is the hallmark of Parkinson’s disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases α-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, α-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and α-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and α-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and α-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between α-synuclein and tau.
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Deng H, Yuan L. Genetic variants and animal models in SNCA and Parkinson disease. Ageing Res Rev 2014; 15:161-76. [PMID: 24768741 DOI: 10.1016/j.arr.2014.04.002] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 04/08/2014] [Accepted: 04/14/2014] [Indexed: 12/20/2022]
Abstract
Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the α-synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The α-synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.
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Affiliation(s)
- Hao Deng
- Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Tongzipo Road 138, Changsha, Hunan 410013, PR China.
| | - Lamei Yuan
- Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Tongzipo Road 138, Changsha, Hunan 410013, PR China
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Heckman MG, Elbaz A, Soto-Ortolaza AI, Serie DJ, Aasly JO, Annesi G, Auburger G, Bacon JA, Boczarska-Jedynak M, Bozi M, Brighina L, Chartier-Harlin MC, Dardiotis E, Destée A, Ferrarese C, Ferraris A, Fiske B, Gispert S, Hadjigeorgiou GM, Hattori N, Ioannidis JPA, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lin CH, Lohmann K, Loriot MA, Lynch T, Mellick GD, Mutez E, Opala G, Park SS, Petrucci S, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Tomiyama H, Uitti RJ, Valente EM, Vassilatis DK, Vilariño-Güell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Xiromerisiou G, Maraganore DM, Farrer MJ, Ross OA. Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiol Aging 2013; 35:266.e5-14. [PMID: 23962496 DOI: 10.1016/j.neurobiolaging.2013.07.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 07/10/2013] [Accepted: 07/15/2013] [Indexed: 11/19/2022]
Abstract
The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
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Abstract
We have witnessed tremendous success in genome-wide association studies (GWAS) in recent years. Since the identification of variants in the complement factor H gene on the risk of age-related macular degeneration, GWAS have become ubiquitous in genetic studies and have led to the identification of genetic variants that are associated with a variety of complex human diseases and traits. These discoveries have changed our understanding of the biological architecture of common, complex diseases and have also provided new hypotheses to test. New tools, such as next-generation sequencing, will be an important part of the future of genetics research; however, GWAS studies will continue to play an important role in disease gene discovery. Many traits have yet to be explored by GWAS, especially in minority populations, and large collaborative studies are currently being conducted to maximize the return from existing GWAS data. In addition, GWAS technology continues to improve, increasing genomic coverage for major global populations and decreasing the cost of experiments. Although much of the variance attributable to genetic factors for many important traits is still unexplained, GWAS technology has been instrumental in mapping over a thousand genes to hundreds of traits. More discoveries are made each month and the scale, quality and quantity of current work has a steady trend upward. We briefly review the current key trends in GWAS, which can be summarized with three goals: increase power, increase collaborations and increase populations.
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Biernacka JM, Armasu SM, Cunningham JM, Ahlskog JE, Chung SJ, Maraganore DM. Do interactions between SNCA, MAPT, and LRRK2 genes contribute to Parkinson's disease susceptibility? Parkinsonism Relat Disord 2011; 17:730-6. [PMID: 21816655 DOI: 10.1016/j.parkreldis.2011.07.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Revised: 06/21/2011] [Accepted: 07/01/2011] [Indexed: 11/26/2022]
Abstract
BACKGROUND Polymorphisms in SNCA, MAPT and LRRK2 genes have recently been confirmed as risk factors for Parkinson's disease (PD), although with small individual attributable risk. Here we investigated the association of PD with interactions between variants of these genes. METHODS As part of a previous study of PD susceptibility genes 119 SNCA, MAPT, and LRRK2 haplotype tagging single nucleotide polymorphisms (SNPs) and two variable number tandem repeats (VNTRs) were genotyped in 1098 PD cases from the upper Midwest, USA and 1098 matched controls. Twenty-six of these SNPs were selected for SNP-SNP (or SNP-VNTR or VNTR-VNTR) interaction analysis (256 interaction pairs). Case-control analyses were performed to study association of pairwise SNP interactions with PD susceptibility. RESULTS Out of the 256 interaction pairs investigated, 10 had uncorrected p-values <0.05. These represented six SNCA-LRRK2 pairs, three SNCA-MAPT pairs, and one MAPT-LRRK2 pair. However, none of these pairwise interactions were significant after correction for multiple testing. Secondary analyses in strata defined by type of control (sibling or unrelated), sex, or age at onset of the case also did not reveal any significant interactions after accounting for multiple testing. CONCLUSIONS This study provides no statistically significant evidence of gene-gene interaction effects for the three confirmed genetic susceptibility loci for PD. However, this does not exclude the possibility that other genomic loci or environmental risk factors interact with these genes.
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Affiliation(s)
- Joanna M Biernacka
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55095, USA
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Pihlstrøm L, Toft M. Genetic variability in SNCA and Parkinson's disease. Neurogenetics 2011; 12:283-93. [PMID: 21800132 DOI: 10.1007/s10048-011-0292-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 07/04/2011] [Indexed: 11/26/2022]
Abstract
Over the last decades, increasing knowledge about the genetic architecture of Parkinson's disease has provided novel insights into the pathogenesis of the disorder, generating hypotheses for further research. Characterizing the role of SNCA, encoding the α-synuclein protein, has been a particularly important aspect of this development. The identification of SNCA as the first gene implicated in monogenic parkinsonism led to the recognition of α-synuclein as a key protein in the pathogenesis and a major component of pathological hallmark lesions. An association between common variants in SNCA and risk of sporadic Parkinson's disease has been established through numerous studies. We review our current understanding of SNCA variability contributing to Parkinson's disease, highlighting the characterization of functionally relevant susceptibility alleles as a major future challenge. We argue that new strategies will be needed to pinpoint the variants that are ultimately responsible for the signals detected in association studies, where targeted resequencing may represent an attractive initial approach.
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Affiliation(s)
- Lasse Pihlstrøm
- Department of Neurology, Oslo University Hospital, Rikshospitalet, P.O. Box 4950, Nydalen, 0424 Oslo, Norway.
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Elbaz A, Ross OA, Ioannidis JPA, Soto-Ortolaza AI, Moisan F, Aasly J, Annesi G, Bozi M, Brighina L, Chartier-Harlin MC, Destée A, Ferrarese C, Ferraris A, Gibson JM, Gispert S, Hadjigeorgiou GM, Jasinska-Myga B, Klein C, Krüger R, Lambert JC, Lohmann K, van de Loo S, Loriot MA, Lynch T, Mellick GD, Mutez E, Nilsson C, Opala G, Puschmann A, Quattrone A, Sharma M, Silburn PA, Stefanis L, Uitti RJ, Valente EM, Vilariño-Güell C, Wirdefeldt K, Wszolek ZK, Xiromerisiou G, Maraganore DM, Farrer MJ. Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 2011; 69:778-92. [PMID: 21391235 DOI: 10.1002/ana.22321] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Revised: 10/18/2010] [Accepted: 10/22/2010] [Indexed: 11/10/2022]
Abstract
OBJECTIVE We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. METHODS Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. RESULTS Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. INTERPRETATION This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects.
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Affiliation(s)
- Alexis Elbaz
- INSERM, U708, Neuroepidemiology, F-75013, Paris, France.
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16
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Wider C, Vilariño-Güell C, Heckman MG, Jasinska-Myga B, Ortolaza-Soto AI, Diehl NN, Crook JE, Cobb SA, Bacon JA, Aasly JO, Gibson JM, Lynch T, Uitti RJ, Wszolek ZK, Farrer MJ, Ross OA. SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study. Eur J Neurol 2010; 18:876-81. [PMID: 21159074 DOI: 10.1111/j.1468-1331.2010.03297.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND PURPOSE Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene-gene interactions between SNCA, MAPT, and GSK3B in association with PD. METHODS Three Caucasian PD patient-control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2-discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. RESULTS Our findings indicate that as previously reported, the SNCA rs356219-G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair-wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219-G and MAPT rs1052553-H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. CONCLUSIONS In the Caucasian patient-control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.
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Affiliation(s)
- C Wider
- Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
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Chung SJ, Armasu SM, Biernacka JM, Lesnick TG, Rider DN, Lincoln SJ, Ortolaza AI, Farrer MJ, Cunningham JM, Rocca WA, Maraganore DM. Common variants in PARK loci and related genes and Parkinson's disease. Mov Disord 2010; 26:280-8. [PMID: 21412835 DOI: 10.1002/mds.23376] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2009] [Revised: 06/08/2010] [Accepted: 07/05/2010] [Indexed: 01/06/2023] Open
Abstract
Rare mutations in PARK loci genes cause Parkinson's disease (PD) in some families and isolated populations. We investigated the association of common variants in PARK loci and related genes with PD susceptibility and age at onset in an outbred population. A total of 1,103 PD cases from the upper Midwest, USA, were individually matched to unaffected siblings (n = 654) or unrelated controls (n = 449) from the same region. Using a sequencing approach in 25 cases and 25 controls, single nucleotide polymorphisms (SNPs) in species-conserved regions of PARK loci and related genes were detected. We selected additional tag SNPs from the HapMap. We genotyped a total of 235 SNPs and two variable number tandem repeats in the ATP13A2, DJ1, LRRK1, LRRK2, MAPT, Omi/HtrA2, PARK2, PINK1, SNCA, SNCB, SNCG, SPR, and UCHL1 genes in all 2,206 subjects. Case-control analyses were performed to study association with PD susceptibility, while cases-only analyses were used to study association with age at onset. Only MAPT SNP rs2435200 was associated with PD susceptibility after correction for multiple testing (OR = 0.74, 95% CI = 0.64-0.86, uncorrected P < 0.0001, log additive model); however, 16 additional MAPT variants, seven SNCA variants, and one LRRK2, PARK2, and UCHL1 variants each had significant uncorrected P-values. There were no significant associations for age at onset after correction for multiple testing. Our results confirm the association of MAPT and SNCA genes with PD susceptibility but show limited association of other PARK loci and related genes with PD.
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Affiliation(s)
- Sun Ju Chung
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
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18
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Lewis KA, Su Y, Jou O, Ritchie C, Foong C, Hynan LS, White CL, Thomas PJ, Hatanpaa KJ. Abnormal neurites containing C-terminally truncated alpha-synuclein are present in Alzheimer's disease without conventional Lewy body pathology. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 177:3037-50. [PMID: 21056999 DOI: 10.2353/ajpath.2010.100552] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The pathological hallmark of Parkinson's disease and diffuse Lewy body disease (DLBD) is the aggregation of α-synuclein (α-syn) in the form of Lewy bodies and Lewy neurites. Patients with both Alzheimer's disease (AD) and cortical Lewy pathology represent the Lewy body variant of AD (LBV) and constitute 25% of AD cases. C-terminally truncated forms of α-syn enhance the aggregation of α-syn in vitro. To investigate the presence of C-terminally truncated α-syn in DLBD, AD, and LBV, we generated and validated polyclonal antibodies to truncated α-syn ending at residues 110 (α-syn110) and 119 (α-syn119), two products of 20S proteosome-mediated endoproteolytic cleavage. Double immunofluorescence staining of the cingulate cortex showed that α-syn110 and α-syn140 (full-length) aggregates were not colocalized in LBV. All aggregates containing α-syn140 also contained α-syn119; however, some aggregates contained α-syn119 without α-syn140, suggesting that α-syn119 may stimulate aggregate formation. Immunohistochemistry and image analysis of tissue microarrays of the cingulate cortex from patients with DLBD (n = 27), LBV (n = 27), and AD (n = 19) and age-matched controls (n = 15) revealed that AD is also characterized by frequent abnormal neurites containing α-syn119. Notably, these neurites did not contain α-syn ending at residues 110 or 122-140. The presence of abnormal neurites containing α-syn119 in AD without conventional Lewy pathology suggests that AD and Lewy body disease may be more closely related than previously thought.
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Affiliation(s)
- Karen A Lewis
- Graduate Program in Molecular Biophysics, Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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Botta-Orfila T, Ezquerra M, Ríos J, Fernández-Santiago R, Cervantes S, Samaranch L, Pastor P, Martí MJ, Muñoz E, Valldeoriola F, Aguilar M, Calopa M, Hernández-Vara J, Tolosa E. Lack of interaction of SNCA and MAPT genotypes in Parkinson's disease. Eur J Neurol 2010; 18:e32. [PMID: 21054681 DOI: 10.1111/j.1468-1331.2010.03245.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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20
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Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Züchner S, Konidari I, Wang G, Singer C, Nahab F, Scott B, Stajich JM, Pericak-Vance M, Haines J, Vance JM, Martin ER. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 2010; 74:97-109. [PMID: 20070850 DOI: 10.1111/j.1469-1809.2009.00560.x] [Citation(s) in RCA: 367] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome-wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies implicated several genes as PD risk loci with strong, but not genome-wide significant, associations. In this study, we combined data from two previously published GWAS of Caucasian subjects with our GWAS of 604 cases and 619 controls for a joint analysis with a combined sample size of 1752 cases and 1745 controls. SNPs in SNCA (rs2736990, p-value = 6.7 x 10(-8); genome-wide adjusted p = 0.0109, odds ratio (OR) = 1.29 [95% CI: 1.17-1.42] G vs. A allele, population attributable risk percent (PAR%) = 12%) and the MAPT region (rs11012, p-value = 5.6 x 10(-8); genome-wide adjusted p = 0.0079, OR = 0.70 [95% CI: 0.62-0.79] T vs. C allele, PAR%= 8%) were genome-wide significant. No other SNPs were genome-wide significant in this analysis. This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD.
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Affiliation(s)
- Todd L Edwards
- John P. Hussman Institute for Human Genomics, University of Miami, FL 33136, USA
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21
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Jellinger KA. Recent advances in our understanding of neurodegeneration. J Neural Transm (Vienna) 2009; 116:1111-62. [DOI: 10.1007/s00702-009-0240-y] [Citation(s) in RCA: 167] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Accepted: 05/05/2009] [Indexed: 12/12/2022]
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Physiological transgene regulation and functional complementation of a neurological disease gene deficiency in neurons. Mol Ther 2009; 17:1517-26. [PMID: 19352323 DOI: 10.1038/mt.2009.64] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The microtubule-associated protein tau (MAPT) and alpha-synuclein (SNCA) genes play central roles in neurodegenerative disorders. Mutations in each gene cause familial disease, whereas common genetic variation at both loci contributes to susceptibility to sporadic neurodegenerative disease. Here, we demonstrate exquisite gene regulation of the human MAPT and SNCA transgene loci and functional complementation in neuronal cell cultures and organotypic brain slices using the herpes simplex virus type 1 (HSV-1) amplicon-based infectious bacterial artificial chromosome (iBAC) vector to express complete loci >100 kb. Cell cultures transduced by iBAC vectors carrying a 143 kb MAPT or 135 kb SNCA locus expressed the human loci similar to the endogenous gene. We focused on analysis of the iBAC-MAPT vector carrying the complete MAPT locus. On transduction into neuronal cultures, multiple MAPT transcripts were expressed from iBAC-MAPT under strict developmental and cell type-specific control. In primary neurons from Mapt(-/-) mice, the iBAC-MAPT vector expressed the human tau protein, as detected by enzyme-linked immunosorbent assay and immunocytochemistry, and restored sensitivity of Mapt(-/-) neurons to Abeta peptide treatment in dissociated neuronal cultures and in organotypic slice cultures. The faithful retention of gene expression and phenotype complementation by the system provides a novel method to analyze neurological disease genes.
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23
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Peuralinna T, Oinas M, Polvikoski T, Paetau A, Sulkava R, Niinistö L, Kalimo H, Hernandez D, Hardy J, Singleton A, Tienari PJ, Myllykangas L. Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein. Ann Neurol 2008; 64:348-52. [PMID: 18661559 DOI: 10.1002/ana.21446] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical beta-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration.
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Affiliation(s)
- Terhi Peuralinna
- Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland
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24
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Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJG, Brown J, Ban M, Spillantini MG, Compston A, Burn DJ, Chinnery PF, Barker RA, Sawcer SJ. Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol 2007; 62:145-53. [PMID: 17683088 DOI: 10.1002/ana.21192] [Citation(s) in RCA: 214] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Parkinson's disease (PD) is a neurodegenerative condition that typically presents as a movement disorder but is known to be associated with variable degrees of cognitive impairment including dementia. We investigated the genetic basis of susceptibility to and cognitive heterogeneity of this disease. METHODS In 659 PD patients, 109 of which were followed up for 3.5 years from diagnosis, and 2,176 control subjects, we studied candidate genes involved in protein aggregation and inclusion body formation, the pathological hallmark of parkinsonism: microtubule-associated protein tau (MAPT), glycogen synthase kinase-3beta (GSK3B), and alpha-synuclein (SNCA). RESULTS We observed that cognitive decline and the development of PD dementia are strongly associated (p = 10(-4)) with the inversion polymorphism containing MAPT. We also found a novel synergistic interaction between the MAPT inversion polymorphism and the single nucleotide polymorphism rs356219 from the 3' region of SNCA. In our data, carrying a risk genotype at either of these loci marginally increases the risk for development of PD, whereas carrying the combination of risk genotypes at both loci approximately doubles the risk for development of the disease (p = 3 x 10(-6)). INTERPRETATION Our data support the hypothesis that tau and alpha-synuclein are involved in shared or converging pathways in the pathogenesis of PD, and suggest that the tau inversion influences the development of cognitive impairment and dementia in patients with idiopathic PD. These findings have potentially important implications for understanding the interface between tau and alpha-synuclein pathways in neurodegenerative disorders and for unraveling the biological basis for cognitive impairment and dementia in PD.
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Affiliation(s)
- An Goris
- Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom.
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25
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Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 2007; 6:652-62. [PMID: 17582365 DOI: 10.1016/s1474-4422(07)70174-6] [Citation(s) in RCA: 225] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The association of six genes with monogenic forms of parkinsonism has unambiguously established that the disease has a genetic component. Of these six genes, LRRK2 (leucine-rich repeat kinase 2, or PARK8), parkin (PARK2), and PINK1 (PTEN-induced putative kinase 1, or PARK6) are the most clinically relevant because of their mutation frequency. Insights from initial familial studies suggest that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive. However, screening of patient cohorts has revealed that up to 70% of people heterozygous for LRRK2 mutations are unaffected, and that more than 50% of patients with mutations in parkin or PINK1 have only a single heterozygous mutation. Deciphering the role of heterozygosity in parkinsonism is important for the development of guidelines for genetic testing, for the counselling of mutation carriers, and for the understanding of late-onset Parkinson's disease. We discuss the roles of heterozygous LRRK2 mutations and heterozygous parkin and PINK1 mutations in the development of parkinsonism, and propose an integrated aetiological model for this complex disease.
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Affiliation(s)
- Christine Klein
- Department of Neurology, University of Lübeck, Lübeck, Germany.
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26
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Abstract
The past 10 years has seen a shift in our etiological concepts of Parkinson's disease, moving from a nearly exclusively environmentally mediated disease towards a complex disorder with important genetic contributors. The identification of responsible mutations in certain genes, particularly alpha-synuclein, Parkin, PINK1, DJ-1 and LRRK2, has increased our understanding of the clinical and pathological changes underlying Parkinson's disease, with implications for patient diagnosis, management and future research. This review will outline the specific genetic advances, discuss their implications for clinical practice and hint at future directions for research into this common and disabling disease.
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Affiliation(s)
- Michael R Douglas
- University of Birmingham Medical School, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK.
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27
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Fung HC, Xiromerisiou G, Gibbs JR, Wu YR, Eerola J, Gourbali V, Hellström O, Chen CM, Duckworth J, Papadimitriou A, Tienari PJ, Hadjigeorgiou GM, Hardy J, Singleton AB. Association of tau haplotype-tagging polymorphisms with Parkinson's disease in diverse ethnic Parkinson's disease cohorts. NEURODEGENER DIS 2007; 3:327-33. [PMID: 17192721 DOI: 10.1159/000097301] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2006] [Accepted: 07/03/2006] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The overlap in the clinical and pathological features of tauopathies and synucleinopathies raises the possibility that the tau protein may be important in Parkinson's disease (PD) pathogenesis. Several MAPT polymorphisms that define the tau H1 haplotype have been investigated for an association with PD with conflicting results; however, two meta-analyses support an association between haplotype H1 and PD. METHODS In this study, we recruited 508 patients and 611 healthy controls from Greek, Finnish and Taiwanese populations. We examined the possible genetic role of variation within MAPT in PD using haplotype-tagging single polymorphisms (SNPs) in these ethnically different PD populations. RESULTS We identified a moderate association at SNP rs3785883 in the Greek cohort for both allele and genotype frequency (p = 0.01, p = 0.05, respectively) as well as for SNP rs7521 (genotype p = 0.02) and rs242557 (p = 0.01 genotypic, p = 0.04 allelic) in the Finnish population. There were no significant differences in genotype or allele distribution between cases and controls in the Taiwanese cohort. CONCLUSION We failed to demonstrate a consistent association between the MAPT H1 haplotype (delineated by intron 9 ins/del) and PD in three ethnically diverse populations. However, the data presented here suggest that subhaplotypes of haplotype H1 may confer susceptibility to PD, and that either allelic heterogeneity or different haplotype composition explain the divergent haplotype results.
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Affiliation(s)
- H C Fung
- Molecular Genetics Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
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28
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Dächsel JC, Mata IF, Ross OA, Taylor JP, Lincoln SJ, Hinkle KM, Huerta C, Ribacoba R, Blazquez M, Alvarez V, Farrer MJ. Digenic parkinsonism: investigation of the synergistic effects of PRKN and LRRK2. Neurosci Lett 2007; 410:80-4. [PMID: 17095157 DOI: 10.1016/j.neulet.2006.06.068] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2006] [Revised: 06/14/2006] [Accepted: 06/30/2006] [Indexed: 11/24/2022]
Abstract
The complex genetic etiology of Parkinson's disease (PD) is indicative of a multifactorial syndrome. A combination of gene-gene and gene-environment interactions may determine a variable phenotypic outcome. Recently a direct gene/protein interaction between two of the most common genetic causes of parkinsonism PRKN and LRRK2 has been postulated. We have identified three Spanish patients simultaneously harboring mutations in PRKN and LRRK2. In comparison to other Spanish patients with a single LRRK2 or PRKN mutation, the three double-mutation patients reported here do not present with an earlier age-at-onset or a faster progression of disease. Although the clinical findings do not support a synergistic effect of LRRK2 and PRKN, a potential genetic interplay might be concealed by the modulating effects of other genes. Nevertheless, this work demonstrates that the presence of mutations in one familial gene should not serve as exclusion criteria in a screen for further genetic variation. Direct interaction of Lrrk2 and parkin proteins was not observed in co-immunoprecipitation pull down experiments. However, in vivo studies are required to assess whether there is an indirect link between Lrrk2 and parkin in disease pathogenesis.
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Affiliation(s)
- Justus C Dächsel
- Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA
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29
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Gálvez-Jiménez N. Parkinson's Disease. Neurobiol Dis 2007. [DOI: 10.1016/b978-012088592-3/50007-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023] Open
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Menéndez J, Rodríguez-Navarro JA, Solano RM, Casarejos MJ, Rodal I, Guerrero R, Sánchez MP, Avila J, Mena MA, de Yébenes JG. Suppression of Parkin enhances nigrostriatal and motor neuron lesion in mice over-expressing human-mutated tau protein. Hum Mol Genet 2006; 15:2045-58. [PMID: 16698879 DOI: 10.1093/hmg/ddl129] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Abnormal deposition of protein tau takes place in the brain of patients with several neurodegenerative diseases. Few of these patients present frontotemporal dementia with parkinsonism and amyotrophy (FTDPA-17), an autosomal dominant tauopathy related to mutations of the gene that codes for protein tau, localized in chromosome 17. The great majority of patients with tauopathies such as Alzheimer's disease, sporadic frontotemporal dementia or progressive supranuclear palsy do not show a Mendelian pattern of inheritance. We have occasionally seen tauopathies in patients with parkin mutations and, therefore, hypothesized that the protein tau interacts with parkin. We have tested that hypothesis in mice with combined genetic modifications of tau (over-expression of human tau with three mutations known to produce FTDPA-17) and parkin (deleted) proteins. Homozygote parkin null or over-expressing mutated-human tau mice have subtle behavioral and molecular abnormalities but do not express a clinical phenotype of neurodegenerative disease. Mice with combined homozygous mutations of these two genes show progressively abnormal walking already noticeable at 3 months of age, loss of dopamine and dopamine markers in striatum, nuclear tau immunoreactive deposits in motor neurons of the spinal cord, abnormal expression of glial markers and enhanced levels of pro-apoptotic proteins; findings that were absent or less pronounced in homozygote animals with deletions of parkin or over-expression of tau. The double transgenic mice do not express normal mechanisms of adaptation to stress such as increased levels of GSH and Hsp-70. In addition, they have reduced levels of CHIP-Hsc70, a complex known to attenuate aggregation of tau and to enhance ubiquitination of phosphorylated tau. We have found high levels of phosphorylated tau in parkin-/-+tau(VLW) mice and a relative decrease of the inactivated pSer9 to total GSK-3 levels. Our data reveal that there are interactions between tau and parkin that could be relevant for the pathogenesis and treatment of tauopathies. Similarly, we hope that the double transgenic parkin-/-+tau(VLW) mice could be useful for testing of compounds with putative therapeutic value in human tauopathies.
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Affiliation(s)
- J Menéndez
- Servicio de Neurobiología, Departamento de Investogación (-1D) Hospital Ramón y Cajal, Spain
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31
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Kwok JBJ, Hallupp M, Loy CT, Chan DKY, Woo J, Mellick GD, Buchanan DD, Silburn PA, Halliday GM, Schofield PR. GSK3B polymorphisms alter transcription and splicing in Parkinson's disease. Ann Neurol 2006; 58:829-39. [PMID: 16315267 DOI: 10.1002/ana.20691] [Citation(s) in RCA: 165] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase-3beta gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3B transcripts that lack exons 9 and 11 (GSKDeltaexon9+11). Increased levels of GSKDeltaexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKDeltaexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene-gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule-associated protein Tau (MAPT) gene (p = 0.009). There was association between a haplotype (T alleles of both GSK3B polymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 individuals: odds ratio, 1.64; p = 0.007; (H1/H1 individuals: odds ratio, 0.68; p < 0.001). Ours results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.
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Affiliation(s)
- John B J Kwok
- Garvan Institute of Medical Research, University of New South Wales, Barker Street, Randwick, Sydney NSW 2031, Australia
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Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Some debate still exists as to whether PD is predominantly environmental or genetic in etiology. The genetic hypothesis of PD etiology has been driven recently by the identification of a number of PD loci. This review deals with each of these loci, discussing the latest data and evidence available. Of particular interest are the recently described mutations in the PINK1 (PARK6) and LRRK2 (PARK8) genes. We also consider the impact of these latest developments on our understanding of sporadic PD and on our everyday practice with PD patients.
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Affiliation(s)
- Alistair J Lewthwaite
- Department of Clinical Neuroscience, School of Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
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Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, Pant PVK, Frazer KA, Cox DR, Ballinger DG. High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 2005; 77:685-93. [PMID: 16252231 PMCID: PMC1271381 DOI: 10.1086/496902] [Citation(s) in RCA: 370] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2005] [Accepted: 07/28/2005] [Indexed: 01/13/2023] Open
Abstract
We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70 x 10(-5)). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07 x 10(-6); P=2.96 x 10(-5)) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility.
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Wenning GK, Jellinger KA. The role of α-synuclein and tau in neurodegenerative movement disorders. Curr Opin Neurol 2005; 18:357-62. [PMID: 16003109 DOI: 10.1097/01.wco.0000168241.53853.32] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Gregor K Wenning
- Department of Neurology, Medical University, Innsbruck, Austria.
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Abstract
PURPOSE OF REVIEW Parkinson's disease is the second most common neurodegenerative disorder and affects 2% of the population over the age of 60 years. Due to the increasing proportion of elderly individuals in developed countries, Parkinson's disease and related neurodegenerative disorders represent a growing burden on the health care system. In the majority of cases, the cause of the disease is still unknown, and its elucidation remains one of the major challenges of the neurosciences. Recent findings in rare genetic forms of Parkinson's disease have allowed the development of novel animal models, providing a basis for a better understanding of the molecular pathogenesis of the disease, setting the stage for the development of novel treatment strategies. RECENT FINDINGS Several novel genes for monogenic forms of Parkinson's disease, such as PINK-1 for an autosomal-recessive early-onset variant, and LRRK2 for a relatively common late-onset autosomal-dominant form have recently been discovered, and several novel animal models have been generated on the basis of genes that had been found earlier. SUMMARY The combination of genetic, pathologic and molecular findings provide increasing evidence that the pathways identified through the cloning of different disease genes are interacting on different levels and share several major pathogenic mechanisms.
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Affiliation(s)
- Thomas Gasser
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
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