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

• Type of Material: Article
• Authors: Meigen Yu, Baylor College of Medicine; Hui Ye, Baylor College of Medicine; Ruth B De-Paula, Baylor College of Medicine; Carl Grant Mangleburg, Baylor College of Medicine; Timothy Wu, Baylor College of Medicine; Tom V Lee, Baylor College of Medicine; Yarong Li, Baylor College of Medicine; Duc Duong, Emory University; Bridget Phillips, Washington University; Carlos Cruchaga, Washington University; Genevera I Allen, Rice University; Nicholas Seyfried, Emory University; Ismael Al-Ramahi, Baylor College of Medicine; Juan Botas, Baylor College of Medicine; Joshua M Shulman, Baylor College of Medicine
• Language: English
• Date: 2023-05-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Yu et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pgen.1010760
• Title of Journal or Parent Work: PLOS GENETICS
• Volume: 19
• Issue: 5
• Start Page: e1010760
• End Page: e1010760
• Grant/Funding Information: JMS, JB, and NTS were supported by grants from the National Institutes of Health (U01AG061357, R01AG057339). JMS was additionally supported by NIH (R21AG068961), Huffington Foundation, the Burroughs Wellcome Foundation (Career Award for Medical Scientists), the Effie Marie Cain Chair in Alzheimer’s Research, a gift from Terry and Bob Lindsay, and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. MY was supported by a grant from the National Institutes of Health (F31NS115364). HY received support from the Parkinson’s Foundation (PF-PRF-830012) and Alzheimer’s Association (AARF-21-848017). The Pathology and Histology Core at Baylor College of Medicine is supported by NIH grant P30CA125123. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: EXPRESSION; NIEMANN-PICK-DISEASE; Science & Technology; PARKINSONS-DISEASE; DROSOPHILA MODEL; GLUCOCEREBROSIDASE; RISK; CLEARANCE; Genetics & Heredity; METAANALYSIS; SERUM-CHOLESTEROL; DEGRADATION; Life Sciences & Biomedicine
• Research Categories: Chemistry, Biochemistry; Health Sciences, Mental Health

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.