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

dc.citation.articleNumbere1010760en_US
dc.citation.issueNumber5en_US
dc.citation.journalTitlePLOS Geneticsen_US
dc.citation.volumeNumber19en_US
dc.contributor.authorYu, Meigenen_US
dc.contributor.authorYe, Huien_US
dc.contributor.authorDe-Paula, Ruth B.en_US
dc.contributor.authorMangleburg, Carl Granten_US
dc.contributor.authorWu, Timothyen_US
dc.contributor.authorLee, Tom V.en_US
dc.contributor.authorLi, Yarongen_US
dc.contributor.authorDuong, Ducen_US
dc.contributor.authorPhillips, Bridgeten_US
dc.contributor.authorCruchaga, Carlosen_US
dc.contributor.authorAllen, Genevera I.en_US
dc.contributor.authorSeyfried, Nicholas T.en_US
dc.contributor.authorAl-Ramahi, Ismaelen_US
dc.contributor.authorBotas, Juanen_US
dc.contributor.authorShulman, Joshua M.en_US
dc.date.accessioned2023-07-21T16:13:57Zen_US
dc.date.available2023-07-21T16:13:57Zen_US
dc.date.issued2023en_US
dc.description.abstractHeterozygous 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.en_US
dc.identifier.citationYu, Meigen, Ye, Hui, De-Paula, Ruth B., et al.. "Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity." <i>PLOS Genetics,</i> 19, no. 5 (2023) Public Library of Science: https://doi.org/10.1371/journal.pgen.1010760.en_US
dc.identifier.digitaljournal-pgen-1010760en_US
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1010760en_US
dc.identifier.urihttps://hdl.handle.net/1911/115004en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of Fair Use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleFunctional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicityen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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