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α-Synuclein amyloid fibril directly binds to LC3B and suppresses SQSTM1/p62-mediated selective autophagy

Cell Research (2024)Cite this article

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Dear Editor,

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, which manifests through the abnormal accumulation of pathological amyloid fibrils composed of α-synuclein (α-syn) into Lewy bodies and the deterioration of dopaminergic neurons in the substantia nigra.1,2,3,4 In addition to α-syn fibrillar aggregation, the disruption of selective autophagy is also tightly linked to the pathogenesis of PD.5,6 The co-localization of LC3B, the key autophagosome protein in selective autophagy,7 and α-syn in the Lewy bodies of PD patients’ brains points towards a potential role of α-syn in modulating selective autophagy.8 Yet, the interplay between them has not been mechanistically elucidated.

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Fig. 1: α-Syn amyloid fibril directly binds LC3B and suppresses SQSTM1/p62-mediated selective autophagy.

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Acknowledgements

This work was supported by the National Natural Science Foundation (NSF) of China (82188101 and 32171236 to C.L.; 92353302 and 32170683 to D.L.; 81925012, 92049301 to B.L.), the Science and Technology Commission of Shanghai Municipality (STCSM) (22JC1410400 to C.L.), the Shanghai Pilot Program for Basic Research — Chinese Academy of Science, Shanghai Branch (JCYJ-SHFY-2022-005 to C.L.), the CAS Project for Young Scientists in Basic Research (YSBR-095 to C.L.), Shanghai Basic Research Pioneer Project to C.L, the Innovation Program of Shanghai Municipal Education Commission (2021-01-07-00-07.E00074 to B.L.). We thank the Cryo-Electron Microscopy center at Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry for help with data collection. We thank the staff members of the Large Protein Preparation System/Nuclear Magnetic Resonance System at the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, Chinese Academy of Sciences for providing technical support and assistance in data collection and analysis.

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Author notes

  1. These authors contributed equally: Qianhui Xu, Huilan Wang.

Authors and Affiliations

  1. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Qianhui Xu, Shengnan Zhang & Cong Liu

  2. University of Chinese Academy of Sciences, Beijing, China

    Qianhui Xu

  3. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, New Cornerstone Science Laboratory, School of Life Sciences, Fudan University, Shanghai, China

    Huilan Wang, Ruonan Yang, Ziying Wang & Boxun Lu

  4. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China

    Youqi Tao & Dan Li

  5. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Bo Sun

  6. Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China

    Dan Li

  7. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Cong Liu

Authors
  1. Qianhui Xu
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  8. Dan Li
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  9. Boxun Lu
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Contributions

C.L., B.L, Q.X. and H.W. designed the project. Q.X. performed in vitro study on molecular mechanism of protein interaction. H.W. performed cellular experiments, verified the role of protein interactions in cell models. R.Y. and Z.W. assisted with cellular experiments. Y.T. and S.Z. assisted with NMR experiments. B.S. and D.L. assisted with data analyses. Q.X. and H.W. prepared figures. Q.X., H.W., B.L. and C.L. wrote the manuscript. All the authors were involved in data analyses and contributed to manuscript discussion and editing. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Boxun Lu or Cong Liu.

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The authors declare no competing interests.

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Xu, Q., Wang, H., Yang, R. et al. α-Synuclein amyloid fibril directly binds to LC3B and suppresses SQSTM1/p62-mediated selective autophagy. Cell Res (2024). https://doi.org/10.1038/s41422-024-01022-2

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