![]() ![]() These intracellular neuronal features contain a cytoplasmic enrichment of the protein alpha-synuclein (α-Syn), thereby defining these diseases as synucleinopathies ( Spillantini et al., 1998a Spillantini et al., 1997). Lewy bodies (LB) and Lewy neurites (LN) are neuropathological hallmarks of Parkinson's disease and other Lewy body disorders. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability. The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). These polymorphs show a radically different structure compared to previously reported polymorphs. We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. Previously, we reported the structure of alpha-synuclein fibrils (residues 1–121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50–57 (Guerrero-Ferreira, eLife 218 7:e36402). Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). ![]()
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