title: Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?
abstract: 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.
authors.affiliation: Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Markopoulou
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Biernacka
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Armasu
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kari J
authors.initials: KJ
authors.lastname: Anderson
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: J Eric
authors.initials: JE
authors.lastname: Ahlskog
authors.affiliation: Department of Biology, University of Nebraska at Omaha, Omaha, NE, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Chase
authors.affiliation: Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Sun Ju
authors.initials: SJ
authors.lastname: Chung
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Farrer
authors.affiliation: Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Frigerio
authors.affiliation: Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA. Electronic address: dmaraganore@northshore.org.
authors.forename: Demetrius M
authors.initials: DM
authors.lastname: Maraganore
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003072:Cognition Disorders / Q000209:etiology; D018900:Dinucleotide Repeats / Q000235:genetics*; D004185:Disability Evaluation; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Outcomes; Parkinson's disease; α-Synuclein gene