LAUSR

Structural Biology Abnormal aggregation of the protein α-synuclein (α-syn) is a hallmark of Parkinson's disease (PD) and several other neurodegenerative disorders. Disease-associated α-syn amyloid fibrils accumulate in Lewy bodies and are often phosphorylated. Phosphorylation at tyrosine 39 (Y39) increased neuropathology in a PD mouse model. Zhao et al. combined chemical synthesis and bacterial expression to prepare α-syn that could be site-specifically phosphorylated at Y39 (pY39). A structure determined by cryo–electron microscopy showed that in the pY39 fibril, the fibril core extends to include the entire N-terminal domain (the core ordinarily starts at around residue 40). Charged residues at the N terminus, including pY39, form a network of interactions in the center of the fibril core. This extended core may explain why pY39 fibrils are resistant to proteolysis, and the structure highlights how posttranslational modifications can affect the structure of fibrils, which in turn mediates their pathology. Proc. Natl. Acad. Sci. U.S.A. 117 , 20305 (2020).