Objective: To determine whether each of the alpha-synucleinopathies has distinct methylation and/or expression profiles that distinguishes them from other disorders in this class.

Background: The alpha-synucleinopathies, encompassing Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are adult-onset neurodegenerative disorders characterized by post-mortem alpha-synuclein (SNCA) aggregate pathology. The clinical features and progression of these disorders, and the brain regions affected, are distinct. SNCA genetic variability has been insightful in monogenic and idiopathic PD but our understanding of gene/protein expression in disease pathogenesis remains limited. How aggregated alpha-synuclein pathology is propagated and why specific cell types are more vulnerable remains enigmatic. Nevertheless, endogenous alpha-synuclein expression modulates the induction of Lewy-like pathology. Genetic variability influences epigenetic marks and allele-specific expression in human induced pluripotent stem cells and differentiated neurons¹. Concomitantly, we have shown that an expanded SNCA (TTTC_n) repeat is associated with dementia in PD². Hence, we hypothesize genetic, epigenetic and expression changes in SNCA influence the distribution and burden of neuropathology in distinct alpha-synucleinopathies.

Methods: Using striatal (affected in PD and MSA-P), cerebellar (affected in MSA-C), entorhinal cortex (affected in DLB) and occipital cortex (unaffected) tissue from brains of clinically- and pathologically-confirmed PD, DLB and MSA along with unaffected control subjects (n=32, 8/group), we pilot genome-wide SNP, methylation and expression analyses. Brain regions are powdered for correlative DNA, RNA and protein extraction. Ampliseq Transcriptome Ion Proton sequencing enables differential gene expression analyses between tissues, patients and control subjects, adjusting for SNPs while considering the burden of inclusion pathology.

Results: We will present a comparison of gene expression profiles of the three alpha-synucleinopathies. Future studies will also assess genetic variability and methylation to determine whether there are distinct profiles for each alpha-synucleinopathy.

Conclusions: The study is to provide insight into the propagation of alpha-synucleinopathies and inform the development of novel therapeutics.

References: 1. Soldner F, Stelzer Y, Shivalila CS, et al. Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression. Nature 2016;533(7601):95-99.

2. Guella I, Evans DM, Szu-Tu C, et al. alpha-synuclein genetic variability: A biomarker for dementia in Parkinson’s disease. Ann Neurol 2016.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-epigenetic-and-expression-profiles-in-alpha-synucleinopathies/