Cryo‐ <scp>EM</scp> structure of a novel α‐synuclein filament subtype from multiple system atrophy
N. Yan, Francisco Candido, Eric Tse, Arthur A. Melo, Stanley B. Prusiner, Daniel A. Mordes, Daniel R. Southworth, Nick A. Paras, Gregory E. Merz
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 I 2 ) in addition to a predominant class comprising MSA Type II 2 filaments. The 3.3‐Å resolution structure of the Type I 2 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.