Glucocerebrosidase rescues alpha-synuclein from amyloid formation in vitro

Alpha-synuclein (αSyn) is a lipid-binding protein that assembles into amyloid fibrils in Parkinson's disease (PD). Lipid binding can accelerate the rate of αSyn fibril formation by stimulating primary nucleation. Recently, the lysosomal protein glucocerebrosidase (GCase) has been identified as a major risk factor in both genetic and sporadic PD. Using solution-state nuclear magnetic resonance spectroscopy, we observe that GCase binds to the C-terminal region of αSyn and attenuates the lipid-binding affinity of αSyn. Mechanistically, this interaction model involves competition between lipids and GCase for αSyn, with lipids and GCase preferentially interacting with the N- and C-terminal regions respectively, in a tug-of-war mechanism. Moreover, the addition of GCase to mature αSyn fibrils increases the NMR-visible population of flexible αSyn, indicating altered fibril-associated αSyn dynamics. Our findings provide a mechanistic explanation for the observed links between changes in GCase abundance and PD.