The emerging role of α-synuclein truncation in aggregation and disease

Abstract

α-Synuclein (asyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. These fibrils may induce further asyn misfolding and propagation of pathologic fibrils in a prion-like process. It is unclear why asyn initially misfolds, but a growing body of literature suggests a critical role of partial proteolytic processing resulting in various truncations of the highly charged and flexible carboxyl-terminal region. This review aims to 1) summarize recent evidence that disease-specific proteolytic truncations of asyn occur in Parkinson's disease, Lewy body dementia, and multiple system atrophy and animal disease models; 2) provide mechanistic insights on how truncation of the amino and carboxyl regions of asyn may modulate the propensity of asyn to pathologically misfold; 3) compare experiments evaluating the prion-like properties of truncated forms ofasyn in various models with implications for disease progression; 4) assess uniquely toxic properties imparted to asyn upon truncation; and 5) discuss pathways through which truncated asyn forms and therapies targeted to interrupt them. Cumulatively, it is evident that truncation of asyn, particularly carboxyl truncation that can be augmented by dysfunctional proteostasis, dramatically potentiates the propensity of αsyn to pathologically misfold into uniquely toxic fibrils with modulated prion-like seeding activity. Therapeutic strategies and experimental paradigms should operate under the assumption that truncation of asyn is likely occurring in both initial and progressive disease stages, and preventing truncation may be an effective preventative strategy against pathologic inclusion formation.