The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

Alpha-synuclein (alpha S) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that alpha S directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of alpha S, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. alpha S associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As alpha S pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters alpha S toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of alpha S function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.

Automated summary

This study reveals the direct modulation of processing bodies by alpha-synuclein, which has significant implications for understanding the pathogenesis of Parkinson's disease. The research found that alpha-synuclein disrupts mRNA decay through interacting with multiple proteins, leading to the dysfunction of relevant pathways. Genetic modulation of P-body components can alter the toxicity of alpha-synuclein, providing a new direction for disease treatment.