Glucocerebrosidase rescues alpha-synuclein from amyloid formation

Abstract Aggregation of the protein α-synuclein (αSyn) Into amyloid fibrils is associated with Parkinson’s disease (PD), a process accelerated by lipids. Recently, the lysosomal protein glucocerebrosidase (GCase) has been identified as a major risk factor in both genetic and sporadic PD. Here, we use solution state NMR to reveal that GCase directly inhibits lipid induced αSyn amyloidogenesis. Structurally, we show that the mechanism for this requires competition between lipids and GCase for αSyn, binding the N and C termini respectively. The affinity of GCase for the C-terminus of αSyn is such that not only does it inhibit lipid induced amyloid formation, but also it destabilizes mature αSyn amyloid fibrils. These results reveal a competitive molecular “tug-of-war” for αSyn termini by GCase and lipid, providing a mechanistic link between the clinically observed links between changes in GCase abundance and Parkinsons disease.