Genetic modifiers of synucleinopathies-lessons from experimental models.

α-Synuclein is a pleiotropic protein underlying a group of progressive neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. Together, these are known as synucleinopathies. Like all neurological diseases, understanding of disease mechanisms is hampered by the lack of access to biopsy tissues, precluding a real-time view of disease progression in the human body. This has driven researchers to devise various experimental models ranging from yeast to flies to human brain organoids, aiming to recapitulate aspects of synucleinopathies. Studies of these models have uncovered numerous genetic modifiers of α-synuclein, most of which are evolutionarily conserved. This review discusses what we have learned about disease mechanisms from these modifiers, and ways in which the study of modifiers have supported ongoing efforts to engineer disease-modifying interventions for synucleinopathies.

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 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.