Does α-Synuclein Have A Dual and Opposing Effect in Preclinical versus 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 1,098 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-8 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.
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ABSTRACT: Expression patterns of the alpha-synuclein gene (SNCA) were studied across anatomy, development, and disease to better characterize its role in the brain. In this postmortem study, negative spatial co-expression between SNCA and 73 interferon-γ (IFN-γ) signaling genes was observed across many brain regions. Recent animal studies have demonstrated that IFN-γ induces loss of dopamine neurons and nigrostriatal degeneration. This opposing pattern between SNCA and IFN-γ signaling genes increases with age (rho = -0.78). In contrast, a meta-analysis of four microarray experiments representing 126 substantia nigra samples reveals a switch to positive co-expression in Parkinson's disease (p<0.005). Use of genome-wide testing demonstrates this relationship is specific to SNCA (p<0.002). This change in co-expression suggests an immunomodulatory role of SNCA that may provide insight into neurodegeneration. Genes showing similar co-expression patterns have been previously linked to Alzheimer's (ANK1) and Parkinson's disease (UBE2E2, PCMT1, HPRT1 and RIT2).PLoS ONE 12/2014; 9(12):e115029. DOI:10.1371/journal.pone.0115029
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ABSTRACT: Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs. Copyright © 2015 Elsevier Ltd. All rights reserved.Parkinsonism & Related Disorders 05/2015; 21(7). DOI:10.1016/j.parkreldis.2015.04.029