Glucosylceramide Associated with Gaucher Disease Forms Amyloid-like Twisted Ribbon Fibrils That Induce α-Synuclein Aggregation.

Abstract

A major risk factor for Gaucher's disease is loss of function mutations in the <i>GBA1</i> gene that encodes lysosomal β-glucocerebrosidase, resulting in accumulation of glucosylceramide (GlcCer), a key lysosomal sphingolipid. <i>GBA1</i> mutations also enhance the risk for Parkinson's disease, whose hallmark is the aggregation of α-synuclein (αSyn). However, the role of accumulated GlcCer in αSyn aggregation is not completely understood. Using various biophysical assays, we demonstrate that GlcCer self-assembles to form amyloid-like fibrillar aggregates <i>in vitro</i>. The GlcCer assemblies are stable in aqueous media of different pH and exhibit a twisted ribbon-like structure. Near lysosomal pH GlcCer aggregates induced αSyn aggregation and stabilized its nascent oligomers. We found that several <i>bona fide</i> inhibitors of proteinaceous amyloids effectively inhibited aggregation of GlcCer. This study contributes to the growing evidence of cross-talk between proteinaceous amyloids and amyloid-like aggregates of metabolites accumulated in diseases and suggests these aggregates as therapeutic targets.