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Insight into Parkinson's Disease from Yeasts: Combined Impact of Genetic Mutations and Covalent Modifications on α‐Synuclein

Parkinson's Disease (PD) is a neurodegenerative disorder linked to the loss of dopaminergic neurons in the midbrain. A key pathological marker within these neurons is the presence of Lewy bodies, which are composed of misfolded α‐synuclein, a protein that is highly post‐translationally modified in both healthy and diseased states. While phosphorylation and nitration of α‐synuclein are well‐studied as contributors to PD pathology, less is known about SUMOylation, acetylation, and glycation. Also, the combined effects of these modifications remain largely unclear, on both wildtype α‐synuclein (which is linked with sporadic PD) and the nine mutant forms of α‐synuclein. Six well‐known mutants cause familial PD (A30P, E46K, H50Q, G51D, A53T, and A53E) and their toxicities are modeled in our well‐established budding yeast system for PD. Three more recently identified α‐synuclein mutants (A18T, A29S, and A53V) are linked with both familial and sporadic PD; but their toxicity mechanisms are poorly understood. Firstly, we report that the A18T, A29S, and A53V mutants are differentially toxic in budding yeast. Second, we have found that SUMOylation is protective and phosphorylation is harmful and they counteract each other in toxicity and cellular localization. Third, our date shows that acetylation is protective and glycation is harmful and they counteracted each other as well. Fourth, when we combined either acetylation or glycation manipulations with SUMOylation and phosphorylation alterations on α‐synuclein, we found that the effects of these modifications were not additive – the impacts of acetylation and glycation depends on phosphorylation status. Fifth, we found that reducing nitration protects against α‐synuclein toxicity and reduces its aggregation in the mutants modified for SUMOylation and phosphorylation. Sixth, we investigated the effects of the familial mutants in tandem with altered acetylation, glycation, or nitration and report two familial mutant‐specific effects: H50Q is surprisingly sensitive and non‐toxic in a hyper‐acetylation environment, while A53E is highly toxic when coupled with hypo‐glycation. Too much nitration also exacerbates toxicity of the familial mutants. Together, these studies done in the simple, yet powerful yeast system, show the relevance of covalent modifications on α‐synuclein forms linked sporadic and familial forms PD, and highlight in‐tandem effects that may underlie toxicity mechanisms.