Both Familial Parkinson's Disease Mutations Accelerate α-Synuclein Aggregation

TLDR

Parkinson’s disease is marked by Lewy bodies composed of α‑synuclein filaments, and two point mutations in α‑synuclein are the only known genetic causes, though their pathogenic mechanism remains unclear. In vitro, both wild‑type and mutant α‑synuclein form insoluble fibrillar aggregates with antiparallel β‑sheet structure at physiological temperature, with the A30P and A53T mutations accelerating aggregation (lag times 180 h and 100 h versus 280 h for wild type), indicating that aggregation may be a critical, mutation‑accelerated step in PD pathogenesis.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major component of which are filaments consisting of α-synuclein. Two recently identified point mutations in α-synuclein are the only known genetic causes of PD, but their pathogenic mechanism is not understood. Here we show that both wild type and mutant α-synuclein form insoluble fibrillar aggregates with antiparallel β-sheet structure upon incubation at physiological temperature <i>in vitro</i>. Importantly, aggregate formation is accelerated by both PD-linked mutations. Under the experimental conditions, the lag time for the formation of precipitable aggregates is about 280 h for the wild type protein, 180 h for the A30P mutant, and only 100 h for the A53T mutant protein. These data suggest that the formation of α-synuclein aggregates could be a critical step in PD pathogenesis, which is accelerated by the PD-linked mutations.