Insight into Parkinson's Disease From a Yeast Model: How Three Alpha‐Synuclein Mutants (A18T, A29S, & A53V) Generate Toxicity

Abstract

Parkinson’s Disease (PD) is a fatal and incurable neurodegenerative disorder linked to the loss of dopaminergic neurons in the midbrain. A key pathological marker of PD is the presence of Lewy bodies, which are composed of misfolded α‐synuclein protein. α‐Synuclein is a highly post‐translationally modified protein in both healthy and diseased states. Modifications on it include phosphorylation, nitration, SUMOylation, acetylation, and glycation. Regulation by lipids is also suggested to modify its toxicity. The toxicity of wildtype α‐synuclein and six well‐known mutant versions linked with familial PD (A30P, E46K, H50Q, G51D, A53T, A53E) is well‐modeled in budding yeast systems. In contrast, the toxicity mechanisms of three newer PD‐linked α‐synuclein mutants (A18T, A29S, and A53V) is poorly understood; particularly, the impact of post‐translational modifications and lipid homeostasis on their toxicity is unknown. Using our lab’s budding yeast model of PD, we investigated the toxicity potential of these three new mutants by assessing the impact of the mutations on yeast growth and α‐synuclein localization in various yeast strains. We report that: 1) All three mutants are toxic to yeast, but to different degrees and, surprisingly, less than wild‐type α‐synuclein; 2) Yeast strains with altered triglycerides reduce α‐synuclein toxicity; 3) Yeasts strains with enhanced acetylation or reduced glycation environments rescue α‐synuclein toxicity; 4) and enhanced SUMOylation is protective against α‐synuclein toxicity; 5) and, finally, yeasts strains deleted for specific PD‐associated genes differentially affect α‐synuclein toxicity. This study expands the evaluation of genetic α‐synuclein mutants linked with PD in yeast models and supports the relevance of covalent modifications, lipid homeostasis, and PD‐associated genes on α‐synuclein toxicity.