Familial Parkinson's Disease Mutant E46Kα-Synuclein Localizes to Membranous Structures, Forms Aggregates, and Induces Toxicity in Yeast Models

摘要

In Parkinson’s disease (PD), midbrain dopaminergic neuronal death is linked to the accumulation of aggregatedα-synuclein. The familial PD mutant form ofα-synuclein, E46K, has not been thoroughly evaluated yet in an organismal model system. Here, we report that E46K resembled wild-type (WT)α-synuclein inSaccharomyces cerevisiaein that it predominantly localized to the plasma membrane, and it did not induce significant toxicity or accumulation. In contrast, inSchizosaccharomyces pombe, E46K did not associate with the plasma membrane. Instead, in one strain, it extensively aggregated in the cytoplasm and was as toxic as WT. Remarkably, in another strain, E46K extensively associated with the endomembrane system and was more toxic than WT. Our studies recapitulate and extend aggregation and phospholipid membrane association properties of E46K previously observedin vitroand cell culture. Furthermore, it supports the notion that E46K generates toxicity partly due to increased association with endomembrane systems within cells.