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Parkinsonism Relat Disord. 2014 Jun;20(6):584-9; discussion 584. doi: 10.1016/j.parkreldis.2014.02.021. Epub 2014 Mar 5.

Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

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Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Department of Biology, University of Nebraska at Omaha, Omaha, NE, USA.
Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.
Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA. Electronic address:


α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression.


Outcomes; Parkinson's disease; α-Synuclein gene

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