Abstract: Background and Objectives MicroRNA (miRNA) changes are observed in PD but remain poorly explored in other ?-synucleinopathies such as MSA. Methods By genome-wide analysis we profiled microRNA expression in serum from 20 MSA cases compared to 40 controls. By qPCR we validated top differentially expressed microRNAs in another sample of 20 MSA and 20 controls. We also assessed the expression of MSA differentially expressed microRNAs in two consecutive sets of 19 and 18 PD patients. Results In the discovery set we identified 25 differentially expressed microRNAs associated with MSA, which are related to prion disease, fatty acid metabolism, and Notch signaling. Among these, we selected nine differentially expressed microRNAs and by qPCR confirmed array findings in a second MSA sample. MicroRNA-7641 and microRNA-191 consistently differentiated between MSA and PD. Conclusions Serum microRNA changes occur in MSA and may reflect disease-associated mechanisms. We identified two microRNAs which may differentiate MSA from PD. © 2020 International Parkinson and Movement Disorder Society

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