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

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 phosphorylation and C-terminal truncations-aggregate and phase separate more rapidly, suggesting hydrophobic exposure. We hypothesize that exposed hydrophobic core in PD-specific αSyn variants not only drives aggregation and phase separation but also promotes promiscuous, non-functional binding to diverse proteins. Using various biochemical and biophysical approaches, we demonstrate that αSynWT engages in functional interactions, whereas C-terminal acidic tail truncated αSyn1-103 and S129-phosphomimicking (S129E) mutant are "reactive," displaying broad, non-functional aberrant binding and impairing chaperone-mediated refolding. Based on our study, we propose a 'Multifactorial Random Disorder Model' outlining how PD-specific αSyn variants drive LB formation through non-functional heterotypic interactions.