Phosphorylation at different sites changes amyloid fibril structure and pathological properties of α-synuclein — ASN Events
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  2. SESSION 5: Amyloids and neurodegenerative diseases
  3. Phosphorylation at different sites changes amyloid fibril structure and pathological properties of α-synuclein

Phosphorylation at different sites changes amyloid fibril structure and pathological properties of α-synuclein (#24)

Yan-Mei Li 1
  1. Department of Chemistry, Tsinghua University, Beiijing, China

α-synuclein (α-syn) plays important roles in the pathology of multiple neurodegenerative diseases. Phosphorylation, as a post-translational modification, has been proposed to regulate the process of synucleinopathies. However, it remains unclear that how phosphorylation at specific sites regulates the structure and properties of α-syn. In this series of work, we synthesized homogeneous α-synuclein with phosphorylation at different sites using expression protein ligation strategy, respectively. Phosphorylation changes strains of α-syn fibrils, leading to distinct fibril characteristics, cellular toxicity1, and cell-to-cell transmission properties of α-synuclein.2 Cryo-EM revealed that phosphorylation at distinct sites results in rearrangements of amyloid fibril structure. These fibril structures explain some properties of different phosphorylated α-syn fibrils and their formation mechanisms.3 This series of work highlights the importance of posttranslational modifications in the progression of degenerative diseases.

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Figure 1.  Phosphorylation at specific sites influences α-syn fibril structure and properties. Left: pS129 enhances α-syn pathological transmission.2 Right: pY39 rearranges α-syn fibril structure.3

  1. Ma, M. R.; Hu, Z. W.; Zhao, Y. F.; Chen, Y. X.; Li, Y. M., Sci. Rep. 2016, 6, 37130.
  2. Zhang, S.; Liu, Y. Q.; Jia, C.; Lim, Y. J.; Feng, G.; Xu, E.; Long, H.; Kimura, Y.; Tao, Y.; Zhao, C.; Wang, C.; Liu, Z.; Hu, J. J.; Ma, M. R.; Liu, Z.; Jiang, L.; Li, D.; Wang, R.; Dawson, V. L.; Dawson, T. M.; Li, Y. M.; Mao, X.; Liu, C., Proc. Natl. Acad. Sci. U. S. A. 2021, 118 (26), e2011196118.
  3. 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., Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (33), 20305-20315.
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