ArticleHuman molecular genetics2009
Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain.
Article in Human molecular genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 109 citations in OpenAlex.
- Head injury, α-synuclein Rep1, and Parkinson's disease.Annals of neurology · 2012Trial
- Synaptic vesicle-omics in mice captures signatures of aging and synucleinopathy.Nature communications · 2025Article
- Article
- Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions.Molecular neurodegeneration · 2025Review
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- Experimental Animal Models of Prodromal Parkinson's Disease.Journal of Parkinson's disease · 2024Review
- Bioinformatics pipeline to guide post-GWAS studies in Alzheimer's: A new catalogue of disease candidate short structural variants.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2023Article
- More than meets the eye in Parkinson's disease and other synucleinopathies: from proteinopathy to lipidopathy.Acta neuropathologica · 2023Review
- Intronic enhancers of the humanScience advances · 2022Article
- Review
- Synaptic vesicle binding of α-synuclein is modulated by β- and γ-synucleins.Cell reports · 2022Article
- Genetic Analysis of Patients With Early-Onset Parkinson's Disease in Eastern China.Frontiers in aging neuroscience · 2022Article
- The Impact ofLife (Basel, Switzerland) · 2021Review
- Genetics of synucleins in neurodegenerative diseases.Acta neuropathologica · 2021Review
- α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease.JCI insight · 2021Article
- iPS Cell-Based Model forFrontiers in cell and developmental biology · 2021Article
- Analysis of Genetic and Non-genetic Predictors of Levodopa Induced Dyskinesia in Parkinson's Disease.Frontiers in pharmacology · 2021Article
- Article
- The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson's Disease.Biomolecules · 2020Review
- Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Alpha-synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.