MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration

α-Synuclein (α-syn) is important in synucleinopathies such as Parkinson's disease (PD). While genome-wide association studies (GWASs) of synucleinopathies have identified many risk loci, the underlying genes have not been shown for most loci. Using Drosophila, we screened 3,471 mutant chromosom...

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Main Authors: Ren, Mengda, Yang, Ying, Heng, Kelsey Hwee Yee, Ng, Lu Yi, Chong, Claris Yuin-Yi, Ng, Yan Ting, Gorur-Shandilya, Srinivas, Lee, Rachel Min Qi, Lim, Kah Leong, Zhang, Jing, Koh, Tong-Wey
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2023
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Online Access:https://hdl.handle.net/10356/164883
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-1648832023-03-05T16:55:27Z MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration Ren, Mengda Yang, Ying Heng, Kelsey Hwee Yee Ng, Lu Yi Chong, Claris Yuin-Yi Ng, Yan Ting Gorur-Shandilya, Srinivas Lee, Rachel Min Qi Lim, Kah Leong Zhang, Jing Koh, Tong-Wey Lee Kong Chian School of Medicine (LKCMedicine) Temasek Life Sciences Laboratory, Singapore Department of Biological Sciences, NUS National Neuroscience Institute, Singapore Science::Medicine Genetic Modifiers Parkinson's Disease α-Synuclein (α-syn) is important in synucleinopathies such as Parkinson's disease (PD). While genome-wide association studies (GWASs) of synucleinopathies have identified many risk loci, the underlying genes have not been shown for most loci. Using Drosophila, we screened 3,471 mutant chromosomes for genetic modifiers of α-synuclein and identified 12 genes. Eleven modifiers have human orthologs associated with diseases, including MED13 and CDC27, which lie within PD GWAS loci. Drosophila Skd/Med13 and glycolytic enzymes are co-upregulated by α-syn-associated neurodegeneration. While elevated α-syn compromises mitochondrial function, co-expressing skd/Med13 RNAi and α-syn synergistically increase the ratio of oxidized-to-reduced glutathione. The resulting neurodegeneration can be suppressed by overexpressing a glycolytic enzyme or treatment with deferoxamine, suggesting that compensatory glycolysis is neuroprotective. In addition, the functional relationship between α-synuclein, MED13, and glycolytic enzymes is conserved between flies and mice. We propose that hypoxia-inducible factor and MED13 are part of a druggable pathway for PD. National Medical Research Council (NMRC) Published version T.-W.K. was supported by National Research Foundation fellowship NRF-NRFF2015- 06. M.R. and K.L.L. were supported by National Medical Research Council Large Collaborative Grant – SPARK2 (L.K.L.). Y.Y. was supported by National Natural Science Foundation of China 82001200 and J.Z. was supported by 81571226, 82020108012, and 81671187. 2023-02-22T02:18:12Z 2023-02-22T02:18:12Z 2022 Journal Article Ren, M., Yang, Y., Heng, K. H. Y., Ng, L. Y., Chong, C. Y., Ng, Y. T., Gorur-Shandilya, S., Lee, R. M. Q., Lim, K. L., Zhang, J. & Koh, T. (2022). MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration. Cell Reports, 41(12), 111852-. https://dx.doi.org/10.1016/j.celrep.2022.111852 2211-1247 https://hdl.handle.net/10356/164883 10.1016/j.celrep.2022.111852 36543134 2-s2.0-85144354562 12 41 111852 en Cell Reports © 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Genetic Modifiers
Parkinson's Disease
spellingShingle Science::Medicine
Genetic Modifiers
Parkinson's Disease
Ren, Mengda
Yang, Ying
Heng, Kelsey Hwee Yee
Ng, Lu Yi
Chong, Claris Yuin-Yi
Ng, Yan Ting
Gorur-Shandilya, Srinivas
Lee, Rachel Min Qi
Lim, Kah Leong
Zhang, Jing
Koh, Tong-Wey
MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration
description α-Synuclein (α-syn) is important in synucleinopathies such as Parkinson's disease (PD). While genome-wide association studies (GWASs) of synucleinopathies have identified many risk loci, the underlying genes have not been shown for most loci. Using Drosophila, we screened 3,471 mutant chromosomes for genetic modifiers of α-synuclein and identified 12 genes. Eleven modifiers have human orthologs associated with diseases, including MED13 and CDC27, which lie within PD GWAS loci. Drosophila Skd/Med13 and glycolytic enzymes are co-upregulated by α-syn-associated neurodegeneration. While elevated α-syn compromises mitochondrial function, co-expressing skd/Med13 RNAi and α-syn synergistically increase the ratio of oxidized-to-reduced glutathione. The resulting neurodegeneration can be suppressed by overexpressing a glycolytic enzyme or treatment with deferoxamine, suggesting that compensatory glycolysis is neuroprotective. In addition, the functional relationship between α-synuclein, MED13, and glycolytic enzymes is conserved between flies and mice. We propose that hypoxia-inducible factor and MED13 are part of a druggable pathway for PD.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Ren, Mengda
Yang, Ying
Heng, Kelsey Hwee Yee
Ng, Lu Yi
Chong, Claris Yuin-Yi
Ng, Yan Ting
Gorur-Shandilya, Srinivas
Lee, Rachel Min Qi
Lim, Kah Leong
Zhang, Jing
Koh, Tong-Wey
format Article
author Ren, Mengda
Yang, Ying
Heng, Kelsey Hwee Yee
Ng, Lu Yi
Chong, Claris Yuin-Yi
Ng, Yan Ting
Gorur-Shandilya, Srinivas
Lee, Rachel Min Qi
Lim, Kah Leong
Zhang, Jing
Koh, Tong-Wey
author_sort Ren, Mengda
title MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration
title_short MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration
title_full MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration
title_fullStr MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration
title_full_unstemmed MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration
title_sort med13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration
publishDate 2023
url https://hdl.handle.net/10356/164883
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