Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson’s disease

Shengnan Zhang, Yu Qing Liu, Chunyu Jia, Yeh Jun Lim, Guoqin Feng, Enquan Xu, Houfang Long, Yasuyoshi Kimura, Youqi Tao, Chunyu Zhao, Chuchu Wang, Zhenying Liu, Jin Jian Hu, Meng Rong Ma, Zhijun Liu, Lin Jiang, Dan Li, Renxiao Wang, Valina L. Dawson, Ted M. DawsonYan Mei Li, Xiaobo Mao, Cong Liu

Research output: Contribution to journalArticlepeer-review


The spread of pathological α-synuclein (α-syn) is a crucial event in the progression of Parkinson’s disease (PD). Cell surface receptors such as lymphocyte activation gene 3 (LAG3) and amyloid precursor-like protein 1 (APLP1) can preferentially bind α-syn in the amyloid over monomeric state to initiate cell-to-cell transmission. However, the molecular mechanism underlying this selective binding is unknown. Here, we perform an array of biophysical experiments and reveal that LAG3 D1 and APLP1 E1 domains commonly use an alkaline surface to bind the acidic C terminus, especially residues 118 to 140, of α-syn. The formation of amyloid fibrils not only can disrupt the intramolecular interactions between the C terminus and the amyloid-forming core of α-syn but can also condense the C terminus on fibril surface, which remarkably increase the binding affinity of α-syn to the receptors. Based on this mechanism, we find that phosphorylation at serine 129 (pS129), a hallmark modification of pathological α-syn, can further enhance the interaction between α-syn fibrils and the receptors. This finding is further confirmed by the higher efficiency of pS129 fibrils in cellular internalization, seeding, and inducing PD-like α-syn pathology in transgenic mice. Our work illuminates the mechanistic understanding on the spread of pathological α-syn and provides structural information for therapeutic targeting on the interaction of α-syn fibrils and receptors as a potential treatment for PD.

Original languageEnglish (US)
Article numbere2011196118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
StatePublished - Jun 29 2021


  • Cell-to-cell transmission
  • Parkinson’s disease
  • Posttranslational modification
  • α-synuclein

ASJC Scopus subject areas

  • General


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