The A53E α-synuclein pathological mutation demonstrates reduced aggregation propensity in vitro and in cell culture

Mutations in the gene that encodes a-synuclein (alpha S) are a known cause of Parkinson's disease. aS is also the major component of pathological inclusions that characterize this disorder and a spectrum of other neurodegenerative diseases termed synucleinopathies. The effects of the most recently identified aS mutation, A53E, on aS aggregation were studied in vitro and in cell culture models. The A53E mutation in aS impedes the formation of aggregated, amyloid protein in vitro compared to wild-type aS. Under certain conditions, A53E aS can still form elongated amyloid fibrils with similar morphology, but with thinner width compared to wild-type aS. Using amyloid seeding of aS in cell culture studies, we demonstrate that significantly less A53E aS could be induced to aggregate compared to wild-type aS, although the mutant protein was still able to form mature inclusions within some cells. Furthermore, expression of A53E alpha S enhanced toxicity in cells experiencing mitochondrial stress. These findings indicate that the A53E mutation in aS reduces the propensity of aS to aggregate both in vitro and in the cellular environment, and may lead to cellular toxicity through other mechanisms. (C) 2015 Elsevier Ireland Ltd. All rights reserved.