Lysosomal ceramides regulate cathepsin B-mediated processing of saposin C and glucocerebrosidase activity.

ABSTRACT: Variants in multiple lysosomal enzymes increase Parkinson's disease (PD) risk, including the genes encoding glucocerebrosidase (GCase), acid sphingomyelinase (ASMase) and galactosylceramidase. Each of these enzymes generates ceramide by hydrolysis of sphingolipids in lysosomes, but the role of this common pathway in PD pathogenesis has not yet been explored. Variations in GBA1, the gene encoding GCase, are the most common genetic risk factor for PD. The lysosomal enzyme cathepsin B has recently been implicated as an important genetic modifier of disease penetrance in individuals harboring GBA1 variants, suggesting a mechanistic link between these enzymes. Here, we found that ceramide activates cathepsin B, and identified a novel role for cathepsin B in mediating prosaposin cleavage to form

SUBMITTER: Kim MJ 

PROVIDER: S-EPMC9307309 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature