Enzyme Activity-Based Genome-wide Screening for Modifiers of Lysosomal Glucocerebrosidase Uncovers Candidate Risk Factors for Parkinson's Disease.
Enzyme Activity-Based Genome-wide Screening for Modifiers of Lysosomal Glucocerebrosidase Uncovers Candidate Risk Factors for Parkinson's Disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Basel, CH · Author affiliation
Roche Pharma Research and Early Development, Neuroscience and Rare Disease Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland.Location evidence
Burnaby, CA · Author affiliation
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.Location evidence
London, GB · Author affiliation
UK Dementia Research Institute at Imperial College London, London SW7 2AZ United Kingdom.Location evidence
Oslo, NO · Author affiliation
Department of Neurology, Oslo University Hospital, Oslo 0424, Norway.Location evidence
Amsterdam, NL · Author affiliation
Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Vrije Universiteit Amsterdam, Amsterdam, 1081 HV Netherlands.Location evidence
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Original 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 an allele of SPNS1 that is associated with increased risk of PD. We show that disruption of SPNS1 does not affect GCase protein levels but impairs its lysosomal function. Collectively, these data suggest that dysfunction of many PD-associated genes converge to impact lysosomal GCase activity and thereby contribute to disease pathogenesis. A better understanding of the impacts of these and the other GCase modulators identified here should help unravel the important, yet complex, relationship between GBA1 and PD.