Parkinson's disease-specific α-Synuclein variants potentially drive Lewy body formation by engaging in promiscuous and non-functional interactions.

ABSTRACT: Lewy bodies (LBs), a pathological hallmark of synucleinopathies, are heterogeneous inclusions that contain α-Synuclein (αSyn) alongside numerous proteins, lipids, and damaged organelles. Current αSyn-fibrillization centric aggregation/phase separation models fail to explain how diverse cellular components are sequestered by disease-specific αSyn variants during LB formation. In the crowded intracellular milieu, proteins constantly encounter one another, but functional protein-protein interactions must outweigh disease-causing 'hydrophobicity' driven non-functional interactions. Although αSyn wild-type (^WT) has a hydrophobic (NAC) core, it is shielded by long-range intramolecular interactions, rendering it "inert." In contrast, Parkinson's disease (PD)-specific αSyn variants-S129

SUBMITTER: Jos S 

PROVIDER: S-EPMC12877186 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature