Comparing alpha-synuclein-interactomes between multiple systems atrophy and Parkinson's disease reveals unique and...

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Primary synucleinopathies, including Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative disorders.
• Alpha-synuclein (αsyn) aggregates phosphorylated at serine 129 (PSER129) are a hallmark, predominantly found in neurons in PD/DLB (neuronal cytoplasmic inclusions) and oligodendroglia in MSA (glial cytoplasmic inclusions).
• The distinct pathological presentations suggest potential differences or overlaps in underlying molecular mechanisms.

Purpose of the Study:

• To investigate and compare the aggregated alpha-synuclein (αsyn) interactomes between MSA and PD/DLB.
• To identify shared and distinct molecular features in the pathogenesis of these synucleinopathies.

Main Methods:

• Utilized the in-situ proximity labeling technique, biotinylation by antibody recognition (BAR), to compare aggregated αsyn-interactomes (BAR-PSER129) and total αsyn-interactomes (BAR-MJFR1).
• Analyzed brain tissue samples from individuals with MSA (n=5) and PD/DLB (n=10), focusing on forebrain and midbrain structures.

Main Results:

• Alpha-synuclein (αsyn) was the most enriched protein in both MSA and PD/DLB samples.
• PD/DLB samples showed significantly more identified interacting proteins (194 for BAR-PSER129, 245 for BAR-MJFR1) compared to MSA (38 for BAR-PSER129, 175 for BAR-MJFR1).
• Pathway analysis revealed distinct mechanisms: PD/DLB involved vesicle/SNARE pathways, while MSA enriched for metabolic/catabolic, iron, and oxidant detoxification pathways, notably involving peroxiredoxins. A shared network of 26 proteins, including SNYGR3 and HSPA8, was identified.

Conclusions:

• Synucleinopathies exhibit both divergent and convergent αsyn-aggregate interactions, indicating 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 a potential common neuronal axonal origin for both MSA and PD/DLB, providing protein interaction maps for these distinct synucleinopathies.