Insight into Parkinson's Disease from Yeasts: Evidence for sumoylation as a protective factor against alpha‐synuclein toxicity

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 mainly composed of misfolded alpha‐synuclein protein. Alpha‐synuclein is a highly post‐translationally modified protein. While the contributions of phosphorylation and nitration of alpha‐synuclein as aids to PD pathology is well studied, less is known about sumoylation, which is proposed to be neuroprotective based on limited studies. The majority of sumoylation takes place on the lysine‐96 and lysine‐102 sites of alpha‐synuclein and it increases the protein's solubility. The goal of this research was to better understand the role of sumoylation in regulating alpha‐synuclein toxicity, and we performed four studies towards it. First, we evaluated the effects of blocking sumoylation on alpha‐synuclein in budding and fission yeast models for PD and found that alpha‐synuclein becomes more aggregated and toxic and localized less at the plasma membrane. Second, we evaluated the effects altering sumoylation pathways by using yeast strains with reduced (ulp1ts) or excessive sumoylation (smt3ts), and found that alpha‐synuclein aggregates more with reduced sumoylation, but becomes less toxic with increased sumoylation. Third, we asked how altering phosphorylation of alpha‐synuclein would alter sumoylation's protective role and found that blocking phosphorylation reduced alpha‐synuclein toxicity. Finally, we evaluated whether blocking sumoylation on familial PD mutant versions of alpha‐synuclein would exacerbate its toxicity; preliminary studies suggest that exacerbation for some, but not all mutants. In the future, we will conduct further studies to understand how sumoylation affects other variants and modifications of alpha‐synuclein.Support or Funding InformationNeuroscience Program and Biology Department, Lake Forest College, Lake Forest, IL 60045