Newly Discovered α-Synuclein Familial Mutant E46K and Key Phosphorylation and Nitrosylation-Deficient Mutants are Toxic to Yeast

Parkinson’s disease is a neurodegenerative disorder that is caused by the loss of dopaminergic neurons in the substantia nigra. Misfolding of αsynuclein is thought to cause this selective cell death. In our α-synuclein yeast overexpression model, we previously demonstrated that α synuclein, is non-toxic to yeast, runs 8-10 kDa higher on protein gels and aggregates minimally in vivo. Recently, a new familial mutant of a-synuclein E46K was discovered. α-Synuclein is a diversely post-translationally modified protein and we hypothesized that one of these modifications may underlie its aberrant size. Here, we show that E46K is more toxic to yeast than other familial α synuclein mutants. α-Synuclein mutants lacking key phosphorylation and nitrosylation sites are surprisingly toxic as well, but do not account for αsynuclein’s aberrant size. Interestingly, all these mutants localize to the periphery of yeast cells and show variable levels of in vivo aggregation.