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

Abstract

Parkinson’s Disease (PD) is a 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 highly post‐translationally modified in 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 (linked with sporadic PD) and the six mutant forms (A30P, E46K, H50Q, G51D, A53T, A53E) linked with early‐onset familial PD. We first evaluated the effects of blocking SUMOylation on α‐synuclein in the well‐established budding yeast model for PD and found that α‐synuclein becomes more toxic and aggregated, losing its membrane localization. Second, we found that SUMOylation and phosphorylation counteract each other in toxicity and localization. Third, we expanded our investigation to two newly reported modifications – acetylation and glycation. We found that acetylation is protective and glycation is harmful. When we combined acetylation or glycation manipulations with SUMOylation and phosphorylation alterations on the α‐synuclein level, we found that the effects of these modifications are not additive – the impacts of acetylation and glycation depends on phosphorylation status. Furthermore, we found that decreased nitration protects against toxicity and reduces α‐syn aggregation in the mutants modifying SUMOylation and phosphorylation. Finally, we investigated the effects of the familial mutants in tandem with altered acetylation, glycation, or nitration. We report two familial mutant‐specific effects: H50Q is surprisingly sensitive and non‐toxic in a hyper‐acetylation environment, while A53E is highly toxic with hypo‐glycation. We also found that too much nitration exacerbates toxicity of the familial mutants relative to low nitration. Specifically, mutant A53T is highly sensitive to excess nitration while H50Q is non‐toxic in such environment. These studies show the relevance of covalent modifications in sporadic and familial PD, and their in‐tandem effects that underlie toxicity mechanisms.Support or Funding InformationYG= supported by Parkinson's foundation‐American Parkinson's disease association, A.B,C.M, A.R and P.J: Research grants from Neurosci