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MED13 and Glycolysis Are Conserved Modifiers of α-Synuclein-Associated Neurodegeneration

64 Pages Posted: 13 Apr 2022 Publication Status: Under Review

See all articles by Mengda Ren

Mengda Ren

Temasek Life Sciences Laboratory

Ying Yang

Zhejiang University - Department of Pathology

Kelsey Hwee Yee Heng

Temasek Life Sciences Laboratory

Lu Yi Ng

Temasek Life Sciences Laboratory

Claris Yuin-Yi Chong

Temasek Life Sciences Laboratory

Yan Ting Ng

Temasek Life Sciences Laboratory

Srinivas Gorur-Shandilya

Brandeis University - Volen National Center for Complex Systems

Rachel Min Qi Lee

National University of Singapore (NUS) - Department of Biological Sciences

Kah Leong Lim

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Jing Zhang

Zhejiang University - Department of Pathology

Tong-Wey Koh

Temasek Life Sciences Laboratory

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Abstract

α-synuclein is important in synucleinopathies such as Parkinson’s disease (PD). While genome wide association studies (GWAS) of synucleinopathies have identified many risk loci, causal genes at most loci remain unknown. Using Drosophila, we screened 3471 mutant chromosomes for genetic modifiers of α-synuclein and identified twelve genes. Eleven modifiers have human orthologs associated with diseases, including MED13 and CDC27 which lie close to PD GWAS loci. Drosophila Skd/Med13 and glycolytic enzymes were co-upregulated by α-synuclein-associated neurodegeneration. While elevated α-synuclein compromised mitochondria function, co-expressing skd/Med13 RNAi and α-synuclein synergistically increased oxidized glutathione. The resulting neurodegeneration was suppressed by overexpressing a glycolytic enzyme and treatment with deferoxamine, suggesting that compensatory glycolysis is neuroprotective. In addition, we show that the functional relationship between α-synuclein, MED13 and glycolytic enzymes is conserved between flies and mice. We propose that an interaction between MED13, a candidate PD risk gene and hypoxia inducible factor represents a druggable pathway.

Keywords: α-Synuclein, MED13, Glycolysis, neurodegeneration, genetic modifiers

Suggested Citation

Ren, Mengda and Yang, Ying and Heng, Kelsey Hwee Yee and Ng, Lu Yi and Chong, Claris Yuin-Yi and Ng, Yan Ting and Gorur-Shandilya, Srinivas and Lee, Rachel Min Qi and Lim, Kah Leong and Zhang, Jing and Koh, Tong-Wey, MED13 and Glycolysis Are Conserved Modifiers of α-Synuclein-Associated Neurodegeneration. Available at SSRN: https://ssrn.com/abstract=4083382 or http://dx.doi.org/10.2139/ssrn.4083382
This version of the paper has not been formally peer reviewed.

Mengda Ren

Temasek Life Sciences Laboratory ( email )

Ying Yang

Zhejiang University - Department of Pathology ( email )

Hangzhou
China

Kelsey Hwee Yee Heng

Temasek Life Sciences Laboratory ( email )

Lu Yi Ng

Temasek Life Sciences Laboratory ( email )

Claris Yuin-Yi Chong

Temasek Life Sciences Laboratory ( email )

Yan Ting Ng

Temasek Life Sciences Laboratory ( email )

Srinivas Gorur-Shandilya

Brandeis University - Volen National Center for Complex Systems ( email )

MA
United States

Rachel Min Qi Lee

National University of Singapore (NUS) - Department of Biological Sciences ( email )

14 Science Drive 4
Singapore, 117543
China

Kah Leong Lim

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine ( email )

Singapore

Jing Zhang

Zhejiang University - Department of Pathology ( email )

Hangzhou
China

Tong-Wey Koh (Contact Author)

Temasek Life Sciences Laboratory ( email )

1 Research Link
117604
Singapore

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