MED13 and Glycolysis Are Conserved Modifiers of α-Synuclein-Associated Neurodegeneration
64 Pages Posted: 13 Apr 2022 Publication Status: Under ReviewMore...
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
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