RRC ID 80969
Author Yu M, Ye H, De-Paula RB, Mangleburg CG, Wu T, Lee TV, Li Y, Duong D, Phillips B, Cruchaga C, Allen GI, Seyfried NT, Al-Ramahi I, Botas J, Shulman JM.
Title Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity.
Journal PLoS Genet
Abstract 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.
Volume 19(5)
Pages e1010760
Published 2023-5-1
DOI 10.1371/journal.pgen.1010760
PMID 37200393
PMC PMC10231792
MeSH Aging / metabolism Animals Animals, Genetically Modified Drosophila / genetics Drosophila / metabolism Glucosylceramidase / genetics Glucosylceramidase / metabolism Humans Lysosomes / metabolism Parkinson Disease* / pathology Transferases (Other Substituted Phosphate Groups) / metabolism alpha-Synuclein* / genetics alpha-Synuclein* / metabolism
Drosophila 7402R-1 7402R-2 7408R-2 7408R-3 10104R-2 10104R-3 6395R-1 6395R-2 3132R-1 3132R-3 8027R-2 8027R-3 15117R-1 15117R-4 2135R-1 31871R-1 31871R-2 6113R-3 12582R-1 12582R-2 5722R-2 5722R-3 12092R-1 12092R-2 31655R-1 31655R-2 3829R-1 3829R-2 4330R-3 4726R-1 4726R-3 15533R-3 7049R-1