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

- A53E mutated α-synuclein displays slowed fibril formation in vitro.
- A53E α-synuclein shows reduced aggregation in cultured cells.
- A53E α-synuclein enhances toxicity in mitochondrially impaired cells.

Mutations in the gene that encodes α-synuclein (αS) are a known cause of Parkinson's disease. αS 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 αS mutation, A53E, on αS aggregation were studied in vitro and in cell culture models. The A53E mutation in αS impedes the formation of aggregated, amyloid protein in vitro compared to wild-type αS. Under certain conditions, A53E αS can still form elongated amyloid fibrils with similar morphology, but with thinner width compared to wild-type αS. Using amyloid seeding of αS in cell culture studies, we demonstrate that significantly less A53E αS could be induced to aggregate compared to wild-type αS, although the mutant protein was still able to form mature inclusions within some cells. Furthermore, expression of A53E αS enhanced toxicity in cells experiencing mitochondrial stress. These findings indicate that the A53E mutation in αS reduces the propensity of αS to aggregate both in vitro and in the cellular environment, and may lead to cellular toxicity through other mechanisms.