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

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dc.citation.articleNumbere1010760
dc.citation.issueNumber5
dc.citation.journalTitlePLOS Genetics
dc.citation.volumeNumber19
dc.contributor.authorYu, Meigen
dc.contributor.authorYe, Hui
dc.contributor.authorDe-Paula, Ruth B.
dc.contributor.authorMangleburg, Carl Grant
dc.contributor.authorWu, Timothy
dc.contributor.authorLee, Tom V.
dc.contributor.authorLi, Yarong
dc.contributor.authorDuong, Duc
dc.contributor.authorPhillips, Bridget
dc.contributor.authorCruchaga, Carlos
dc.contributor.authorAllen, Genevera I.
dc.contributor.authorSeyfried, Nicholas T.
dc.contributor.authorAl-Ramahi, Ismael
dc.contributor.authorBotas, Juan
dc.contributor.authorShulman, Joshua M.
dc.date.accessioned2023-07-21T16:13:57Z
dc.date.available2023-07-21T16:13:57Z
dc.date.issued2023
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.
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.
dc.identifier.digitaljournal-pgen-1010760
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1010760
dc.identifier.urihttps://hdl.handle.net/1911/115004
dc.language.isoeng
dc.publisherPublic Library of Science
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.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleFunctional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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