Structural and functional characterization of two alpha-synuclein strains

TLDR

α‑Synuclein aggregation is linked to Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure, and multiple system atrophy, and, like prion diseases, distinct strains of the same protein may underlie differing clinical phenotypes and disease progression. The study aims to structurally and functionally characterize two polymorphs of α‑synuclein. The authors demonstrate that the two polymorphs satisfy the molecular criteria for distinct α‑synuclein strains, exhibiting divergent structures, toxicity levels, and in vitro and in vivo seeding and propagation properties.

Abstract

α-Synuclein aggregation is implicated in a variety of diseases including Parkinson's disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway. Here we structurally and functionally characterize two polymorphs of α-synuclein. We present evidence that the two forms indeed fulfil the molecular criteria to be identified as two strains of α-synuclein. Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies.