Structures of α-synuclein filaments from multiple system atrophy

Abstract

Synucleinopathies are human neurodegenerative diseases that include multiple system atrophy (MSA), Parkinsons disease, Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) (1). Existing treatments are at best symptomatic. These diseases are characterised by the presence in brain cells of filamentous inclusions of -synuclein, the formation of which is believed to cause disease (2, 3). However, the structures of -synuclein filaments from human brain are not known. Here we show, using electron cryo-microscopy, that -synuclein inclusions from MSA are made of two types of filaments, each of which consists of two different protofilaments. Non-proteinaceous molecules are present at the protofilament interfaces. By two-dimensional class averaging, we show that -synuclein filaments from the brains of patients with MSA and DLB are different, suggesting that distinct conformers (or strains) characterise synucleinopathies. As was the case of tau assemblies (4-9), the structures of -synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, with implications for understanding the mechanisms of aggregate propagation and neurodegeneration in human brain. These findings have diagnostic and potential therapeutic relevance, especially in view of the unmet clinical need to be able to image filamentous -synuclein inclusions in human brain.