Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein mediated neurodegeneration

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinsons disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 88 conserved fly homologs of 38 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by -synuclein (Syn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of Syn-induced progressive locomotor dysfunction, following knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles support dose-sensitivity and context-dependent pleiotropy in the presence or absence of Syn. Homologs of 2 genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of Syn-induced brain structural degeneration. The enzymes encoded by several modifier genes are upregulated in Syn transgenic flies, based on unbiased proteomics, revealing a possible compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in Syn-mediated neurodegeneration.