Cryo-EM structure of a novel α-synuclein filament subtype from multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by accumulation of α-synuclein cross-β amyloid filaments in the brain. Previous structural studies of these filaments by cryo-electron microscopy (cryo-EM) revealed three discrete folds distinct from α-synuclein filaments associated with other neurodegenerative diseases. Here, we use cryo-EM to identify a novel, low-populated MSA filament subtype (designated Type I₂) in addition to a predominant class comprising MSA Type II₂ filaments. The 3.3-Å resolution structure of the Type I₂ filament reveals a fold consisting of two asymmetric protofilaments, one of which adopts a novel structure that is chimeric between two previously reported protofilaments. These results further define MSA-specific folds of α-synuclein filaments and have implications for designing MSA diagnostics and therapeutics.

Keywords: cryo‐electron microscopy; multiple system atrophy; neurodegeneration; prion; protein aggregation; α‐synuclein.