Structure of a novel α-synuclein filament fold from multiple system atrophy

Multiple system atrophy (MSA) is a synucleinopathy, a group of related diseases characterized by the accumulation of α-synuclein aggregates in the brain. In MSA, these aggregates form glial cytoplasmic inclusions, which contain abundant cross-β amyloid filaments. Structures of α-synuclein filaments isolated from MSA patient tissue were determined by cryo–electron microscopy (cryo-EM), revealing three discrete folds that are distinct from α-synuclein filaments associated with other synucleinopathies. Here, we use cryo-EM classification methods to characterize filaments from one individual with MSA and identify a novel, low-populated MSA filament fold (designated Type I ₂ ) in addition to a predominant class comprising MSA Type II ₂ . The 3.3-Å resolution structure of the Type I ₂ filament reveals a fold consisting of two asymmetric protofilaments. One is identical to a previously solved Type I protofilament, while the second adopts a novel fold that is chimeric between two previously reported Type I and II protofilaments. These results further define disease-specific folds of α-synuclein filaments that develop in MSA and have implications for the design of therapeutic and diagnostic molecules that target disease.