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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 susce...

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Autores principales: Yu, Meigen, Ye, Hui, De-Paula, Ruth B., Mangleburg, Carl Grant, Wu, Timothy, Lee, Tom V., Li, Yarong, Duong, Duc, Phillips, Bridget, Cruchaga, Carlos, Allen, Genevera I., Seyfried, Nicholas T., Al-Ramahi, Ismael, Botas, Juan, Shulman, Joshua M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231792/
https://www.ncbi.nlm.nih.gov/pubmed/37200393
http://dx.doi.org/10.1371/journal.pgen.1010760
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author Yu, Meigen
Ye, Hui
De-Paula, Ruth B.
Mangleburg, Carl Grant
Wu, Timothy
Lee, Tom V.
Li, Yarong
Duong, Duc
Phillips, Bridget
Cruchaga, Carlos
Allen, Genevera I.
Seyfried, Nicholas T.
Al-Ramahi, Ismael
Botas, Juan
Shulman, Joshua M.
author_facet Yu, Meigen
Ye, Hui
De-Paula, Ruth B.
Mangleburg, Carl Grant
Wu, Timothy
Lee, Tom V.
Li, Yarong
Duong, Duc
Phillips, Bridget
Cruchaga, Carlos
Allen, Genevera I.
Seyfried, Nicholas T.
Al-Ramahi, Ismael
Botas, Juan
Shulman, Joshua M.
author_sort Yu, Meigen
collection PubMed
description 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.
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spelling pubmed-102317922023-06-01 Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity Yu, Meigen Ye, Hui De-Paula, Ruth B. Mangleburg, Carl Grant Wu, Timothy Lee, Tom V. Li, Yarong Duong, Duc Phillips, Bridget Cruchaga, Carlos Allen, Genevera I. Seyfried, Nicholas T. Al-Ramahi, Ismael Botas, Juan Shulman, Joshua M. PLoS Genet Research Article 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. Public Library of Science 2023-05-18 /pmc/articles/PMC10231792/ /pubmed/37200393 http://dx.doi.org/10.1371/journal.pgen.1010760 Text en © 2023 Yu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Yu, Meigen
Ye, Hui
De-Paula, Ruth B.
Mangleburg, Carl Grant
Wu, Timothy
Lee, Tom V.
Li, Yarong
Duong, Duc
Phillips, Bridget
Cruchaga, Carlos
Allen, Genevera I.
Seyfried, Nicholas T.
Al-Ramahi, Ismael
Botas, Juan
Shulman, Joshua M.
Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
title Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
title_full Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
title_fullStr Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
title_full_unstemmed Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
title_short Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
title_sort functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231792/
https://www.ncbi.nlm.nih.gov/pubmed/37200393
http://dx.doi.org/10.1371/journal.pgen.1010760
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