Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity.

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's 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 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including 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 suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, 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 αSyn-mediated neurotoxicity. Author summary: Parkinson's disease (PD) is characterized clinically by progressive decline in both motor and non-motor brain functions, and pathologically by the aggregation of alpha-synuclein protein along with neuron loss. Partial loss-of-function in the glucocerebrosidase (GBA) gene causes a 5-fold increased risk of PD. By contrast, nearly complete loss of GBA causes a distinct disorder called Gaucher's disease, and other metabolic genes that cause lysosomal storage disorders (LSDs) have been similarly implicated in PD risk. Using a fruit fly model, we have tested 86 conserved homologs of human LSD genes for interactions with alpha-synuclein-induced neurotoxicity. Our screen identified 15 enhancers of progressive locomotor dysfunction, including knockdown of fly homologs of GBA, other LSD genes with support from human genetics, as well as new candidate PD genes, such as LIPA and NPC1, which are involved in cholesterol metabolism. Our results suggest that partial loss of many LSD genes may enhance alpha-synuclein-mediated PD risk and pathogenesis, whereas more complete loss impairs nervous system function independent of alpha-synuclein. We also discover that alpha-synuclein may trigger increases of selected LSD proteins. Overall, this work reinforces the important role of lysosomal metabolism in brain health and PD pathogenesis. [ABSTRACT FROM AUTHOR]