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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-05-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010760 |
| _version_ | 1797802636401967104 |
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| author | Meigen Yu Hui Ye Ruth B De-Paula Carl Grant Mangleburg Timothy Wu Tom V Lee Yarong Li Duc Duong Bridget Phillips Carlos Cruchaga Genevera I Allen Nicholas T Seyfried Ismael Al-Ramahi Juan Botas Joshua M Shulman |
| author_facet | Meigen Yu Hui Ye Ruth B De-Paula Carl Grant Mangleburg Timothy Wu Tom V Lee Yarong Li Duc Duong Bridget Phillips Carlos Cruchaga Genevera I Allen Nicholas T Seyfried Ismael Al-Ramahi Juan Botas Joshua M Shulman |
| author_sort | Meigen Yu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T05:09:43Z |
| format | Article |
| id | doaj.art-2fca0b159dad43719f3d2b2f9cfef08b |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-03-13T05:09:43Z |
| publishDate | 2023-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-2fca0b159dad43719f3d2b2f9cfef08b2023-06-16T05:30:55ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-05-01195e101076010.1371/journal.pgen.1010760Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity.Meigen YuHui YeRuth B De-PaulaCarl Grant MangleburgTimothy WuTom V LeeYarong LiDuc DuongBridget PhillipsCarlos CruchagaGenevera I AllenNicholas T SeyfriedIsmael Al-RamahiJuan BotasJoshua M ShulmanHeterozygous 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.https://doi.org/10.1371/journal.pgen.1010760 |
| spellingShingle | Meigen Yu Hui Ye Ruth B De-Paula Carl Grant Mangleburg Timothy Wu Tom V Lee Yarong Li Duc Duong Bridget Phillips Carlos Cruchaga Genevera I Allen Nicholas T Seyfried Ismael Al-Ramahi Juan Botas Joshua M Shulman Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity. PLoS Genetics |
| 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 |
| url | https://doi.org/10.1371/journal.pgen.1010760 |
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