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

[Image: see text] A major risk factor for Gaucher’s disease is loss of function mutations in the GBA1 gene that encodes lysosomal β-glucocerebrosidase, resulting in accumulation of glucosylceramide (GlcCer), a key lysosomal sphingolipid. GBA1 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 in vitro. 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 bona fide 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.