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bioRxiv · 10.1101/2020.04.13.040261

Parkinson's disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM

Zhao, K.·Lim, Y.-J.·Liu, Z.·Long, H.·Sun, Y.·Hu, J.-J.·Zhao, C.·Tao, Y.·Zhang, X.·Li, D.·Li, Y.-M.·Liu, C.
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Abstract

Post-translational modifications (PTMs) of -synuclein (-syn), e.g. phosphorylation, play an important role in modulating -syn pathology in Parkinsons disease (PD) and -synucleinopathies. Accumulation of phosphorylated -syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to -syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous -syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-EM structure of pY39 -syn fibril, which reveals a new fold of -syn with pY39 in the center of the fibril core forming electrostatic interaction network with eight charged residues in the N-terminal region of -syn. This structure composed of residues 1-100 represents the largest -syn fibril core determined so far. This work provides structural understanding on the pathology of pY39 -syn fibril, and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.

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Zhao, K., Lim, Y.-J., Liu, Z., Long, H., Sun, Y., Hu, J.-J., Zhao, C., Tao, Y., Zhang, X., Li, D., Li, Y.-M., Liu, C.. 2020-04-14. Parkinson's disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM. https://doi.org/10.1101/2020.04.13.040261

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