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 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 tha

SUBMITTER: Paul A 

PROVIDER: S-EPMC8397424 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature