Enzyme Activity-Based Genome-wide Screening for Modifiers of Lysosomal Glucocerebrosidase Uncovers Candidate Risk Factors for Parkinson's Disease.

ABSTRACT: Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase (GCase), are the strongest common genetic risk factor for Parkinson's Disease (PD). However, these mutations are incompletely penetrant, which suggests that there are likely genetic modifiers of GCase function. To identify such genes, we implemented a live cell GCase activity-based CRISPR-platform to enable genome-wide screening for novel regulators of lysosomal GCase activity. Among the screening hits, we find significant enrichment of genes linked to development and progression of PD through genome-wide association studies (GWAS). Moreover, we identify two lysosomal lipid transporter genes, including those encoding the lysosphospholipid transporter SPNS1 and the cholesterol transporter NPC1, and find a

SUBMITTER: Udayar V 

PROVIDER: S-EPMC12550621 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature