Author(s): Meigen Yu, Baylor College of Medicine; Meigen Yu, Baylor College of Medicine; Ismael Al-Ramahi, Baylor College of Medicine; Juan Botas, Baylor College of Medicine; Joshua Shulman, Baylor College of Medicine //

ABSTRACT: Parkinson’s disease (PD) is a common and incurable neurodegenerative disorder with strong evidence for heritability. GBA is one of the most common genetic risk factors for PD, with carriers of loss-of-function variants having a 5- to 10-fold increased risk of PD. Complete loss of GBA causes a metabolic disorder called Gaucher’s disease, one in a group of over 50 rare diseases called lysosomal storage disorders (LSDs). In an exome-wide association study including 1156 subjects with PD, we discovered a significant variant burden among 53 LSD gene loci in addition to GBA, suggesting that other LSD genes also contribute to PD risk. To investigate further, I have utilized a Drosophila transgenic model to experimentally confirm which LSD genes likely modify PD pathogenesis. In flies, pan-neuronal over-expression of human α-synuclein induces Lewy body-like PD pathology along with progressive, age-dependent neurodegeneration and locomotor impairment. Using more than 300 independent RNA-interference strains, I knocked down 94 conserved LSD genes and screened for enhancers or suppressors of α-synuclein-mediated neurodegeneration. My screen has identified 15 genetic modifiers whose knockdown strongly enhances the α-synuclein-associated locomotor phenotype, including homologs of well-established PD risk genes (e.g. GBA, SCARB2, and SMPD1), as well as many novel gene candidates (ARSB, IDS, IDUA, LIPA, and NPC1). I have also identified that loss-of-function alleles for homologs of DNAJC5 and NPC1 enhance the α-synuclein locomotor phenotype in heterozygosity, implicating that modification of α-synuclein toxicity may be dose-dependent. Altogether, I have identified three metabolic pathways of interest: regulation of ceramides and sphingolipids, breakdown of glycosaminoglycans, and trafficking/metabolism of cholesterol. Interestingly, the metabolites involved in these pathways constitute major components of lipid rafts, which are particularly important as organizing structures at the synaptic membrane. I have also further confirmed that knockdown or heterozygous loss of cholesterol metabolism gene homologs NPC1 and LIPA enhance α-synuclein toxicity in an independent model of retinal neurodegeneration, highlighting the possible importance of investigating cholesterol metabolism in PD pathology. Altogether, my results support a model in which dose-dependent loss of LSD gene function increases PD risk by promoting α-synuclein toxicity in neurons, and further highlight a central role for the lysosome and lipid metabolism in PD pathogenesis.

Source of Funding: NINDS (F31 NS115364-02)