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

Alpha-synuclein (alpha-syn) is important in synucleinopathies such as Parkinson’s disease (PD). While genome-wide association studies (GWAS) of synucleinopathies have identified many risk loci, the underlying genes remain unknown for most loci. Using Drosophila, we screened 3471 mutant chromosomes for genetic modifiers of alpha-synuclein and identified twelve 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 alpha-syn-associated neurodegeneration. While elevated alpha-syn compromises mitochondrial function, co-expressing skd/Med13 RNAi and alpha-syn synergistically increases 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 alpha-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.