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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/164883 |
| _version_ | 1826115284471119872 |
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| 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 |
| 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 |
| author_sort | Ren, Mengda |
| collection | NTU |
| 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. |
| first_indexed | 2024-10-01T03:52:57Z |
| format | Journal Article |
| id | ntu-10356/164883 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:52:57Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-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 |
| 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 |
| title | 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_short | MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration |
| title_sort | med13 and glycolysis are conserved modifiers of α synuclein associated neurodegeneration |
| topic | Science::Medicine Genetic Modifiers Parkinson's Disease |
| url | https://hdl.handle.net/10356/164883 |
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