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The molecular pathogenesis of degenerative parkinsonisms, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and Multiple system atrophy (MSA), remains largely unknown. To gain novel insight into molecular processes associated with these diseases, we conducted a proteome-wide expression study in prefrontal cortex tissue from a cohort of 181 individuals, comprising PD (N = 73), PSP (N = 18), MSA (N = 17) and healthy control (N = 73). Using marker gene profiles, we first assess the cellular composition of the samples and, subsequently, identify distinct protein signatures for each disease, while correcting for cell composition. Our findings indicate that all three diseases are characterized by a structural and/or functional loss of deep cortical neurons, while PD exhibits an additional decrease in somatostatin-expressing interneurons, as well as in endothelial cells. Differential protein expression analysis identified multiple proteins and pathways with disease-specific expression, some of which have previously been associated with parkinsonism or neurodegeneration in general. Notably, we observed a strong mitochondrial signature which was present in both PD and PSP, albeit of a different composition and most pronounced in PSP, but not in MSA where immunological/inflammation-related pathways dominated. Additionally, we identified protein signatures associated with the severity of α-synuclein pathology in PD and showed that these are highly enriched in an upregulation of mitochondrial processes, specifically related to oxidative phosphorylation and in particular respiratory complexes I and IV. We identify multiple novel signatures of protein expression, associated with PD, PSP, and MSA, as well as with the severity of α-synuclein pathology in the PD brain.
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