Glucocerebrosidase rescues alpha-synuclein from amyloid formation

Abstract

Aggregation of the protein -synuclein (Syn) Into amyloid fibrils is associated with Parkinsons 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 Syn amyloidogenesis. Structurally, we show that the mechanism for this requires competition between lipids and GCase for Syn, binding the N and C termini respectively. The affinity of GCase for the C-terminus of Syn is such that not only does it inhibit lipid induced amyloid formation, but also it destabilizes mature Syn amyloid fibrils. These results reveal a competitive molecular \"tug-of-war\" for Syn termini by GCase and lipid, providing a mechanistic link between the clinically observed links between changes in GCase abundance and Parkinsons disease.