Proximity proteomics reveals unique and shared pathological features between multiple system atrophy and Parkinson's...

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Synucleinopathies (Parkinson's disease, dementia with Lewy bodies, multiple system atrophy) share clinical and pathological features, primarily alpha-synuclein (αsyn) aggregates phosphorylated at serine 129 (PSER129).
• Distinct cellular localization of PSER129 aggregates (neurons in PD/DLB vs. oligodendroglia in MSA) suggests unique or shared pathological processes.

Purpose of the Study:

• To compare aggregated and total αsyn interactomes between MSA and PD/DLB using in-situ proximity labeling.
• To elucidate the unique and shared molecular mechanisms underlying different synucleinopathies.

Main Methods:

• Employed biotinylation by antibody recognition (BAR) to identify αsyn interactomes (BAR-PSER129 and BAR-MJFR1) in MSA and PD/DLB brain tissues.
• Utilized comparative proteomics and pathway enrichment analysis to identify differentially abundant proteins and associated pathways.

Main Results:

• Identified 79 PD/DLB-differentially abundant proteins and 3 MSA-differentially abundant proteins (CBR1, CRYAB, GFAP).
• PD/DLB interactomes were enriched for vesicle/SNARE pathways, while MSA was enriched for metabolic, iron, and oxidant detoxification pathways, notably peroxiredoxins.
• A shared network of 26 proteins, including SYNGR3 and HSPA8, was identified between MSA and PD/DLB; extracellular exosome pathways were universally enriched.

Conclusions:

• Synucleinopathies exhibit divergent and convergent αsyn-aggregate interactions, indicating both unique and shared pathogenic mechanisms.
• MSA pathogenesis uniquely involves glial oxidant detoxification, whereas PD/DLB pathogenesis is dominated by neuronal vesicular processes.
• Shared interactions suggest neuronal axons may be the origin for both MSA and PD/DLB, providing novel αsyn protein interaction maps for synucleinopathies.