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Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are neurodegenerative diseases with shared clinical and pathological features. Aggregates of alpha-synuclein (αsyn) phosphorylated at serine 129 (PSER129) are hallmarks of synucleinopathies, which, for PD/DLB, are found predominantly in neurons, whereas in MSA, aggregates are primarily found in oligodendroglia. It remains unclear whether the distinct pathological presentations of PD/DLB and MSA are manifestations of unique or shared pathological processes. Using the in-situ proximity labeling technique of biotinylation by antibody recognition (BAR), we compared aggregated αsyn-interactomes (BAR-PSER129) and total αsyn-interactomes (BAR-MJFR1) between MSA (n = 5) and PD/DLB (n = 10) in forebrain and midbrain structures. Comparison between MSA and PD/DLB-enriched proteins revealed 79 PD/DLB-differentially abundant proteins and only three MSA-differentially abundant proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed that vesicle/SNARE-associated pathways dominated PD/DLB interactions, whereas MSA was strongly enriched for metabolic/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathway enrichment in MSA. A network of 26 proteins, including neuronal-specific proteins (e.g., SYNGR3) with HSPA8 at the core, was shared between MSA and DLB/PD. Extracellular exosome pathways were universally enriched regardless of the disease or BAR target protein. In conclusion, synucleinopathies have divergent and convergent αsyn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD/DLB. Shared interactions, specifically SYNGR3, between MSA and PD/DLB suggest that neuronal axons are the origin of both diseases. In conclusion, we provide αsyn protein interaction maps for two distinct synucleinopathies.
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