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Mechanistic basis for receptor-mediated pathological alpha-synuclein fibril cell-to-cell transmission in Parkinson's disease
Zhang, Shengnan; Liu, Yu-Qing; Jia, Chunyu; Lim, Yeh-Jun; Feng, Guoqin; Xu, Enquan; Long, Houfang; Kimura, Yasuyoshi; Tao, Youqi; Zhao, Chunyu; Wang, Chuchu; Liu, Zhenying; Hu, Jin-Jian; Ma, Meng-Rong; Liu, Zhijun; Jiang, Lin; Li, Dan; Wang, Renxiao; Dawson, Valina L.; Dawson, Ted M.; Li, Yan-Mei; Mao, Xiaobo; Liu, Cong
2021
Source PublicationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN0027-8424
Volume118Issue:26
AbstractThe spread of pathological alpha-synuclein (alpha-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 alpha-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 alpha-syn. The formation of amyloid fibrils not only can disrupt the intramolecular interactions between the C terminus and the amyloid-forming core of alpha-syn but can also condense the C terminus on fibril surface, which remarkably increase the binding affinity of alpha-syn to the receptors. Based on this mechanism, we find that phosphorylation at serine 129 (pS129), a hallmark modification of pathological alpha-syn, can further enhance the interaction between alpha-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 alpha-syn pathology in transgenic mice. Our work illuminates the mechanistic understanding on the spread of pathological alpha-syn and provides structural information for therapeutic targeting on the interaction of alpha-syn fibrils and receptors as a potential treatment for PD.
Document Type期刊论文
Identifierhttp://ir.sari.ac.cn/handle/39PL6PPA/3388
Collection中国科学院上海高等研究院
Recommended Citation
GB/T 7714
Zhang, Shengnan,Liu, Yu-Qing,Jia, Chunyu,et al. Mechanistic basis for receptor-mediated pathological alpha-synuclein fibril cell-to-cell transmission in Parkinson's disease[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2021,118(26).
APA Zhang, Shengnan.,Liu, Yu-Qing.,Jia, Chunyu.,Lim, Yeh-Jun.,Feng, Guoqin.,...&Liu, Cong.(2021).Mechanistic basis for receptor-mediated pathological alpha-synuclein fibril cell-to-cell transmission in Parkinson's disease.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,118(26).
MLA Zhang, Shengnan,et al."Mechanistic basis for receptor-mediated pathological alpha-synuclein fibril cell-to-cell transmission in Parkinson's disease".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 118.26(2021).
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