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Molecular Mechanism for the Suppression of Alpha Synuclein Membrane Toxicity by an Unconventional Extracellular Chaperone

  • Rashik Ahmed
    Rashik Ahmed
    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton ON L8S 4M1, Canada
    More by Rashik Ahmed
  • Jinfeng Huang
    Jinfeng Huang
    Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada
  • Daniel K. Weber
    Daniel K. Weber
    Department of Biochemistry, Chemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, United States
  • Tata Gopinath
    Tata Gopinath
    Department of Biochemistry, Chemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, United States
  • Gianluigi Veglia
    Gianluigi Veglia
    Department of Biochemistry, Chemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, United States
  • Madoka Akimoto
    Madoka Akimoto
    Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada
  • Adree Khondker
    Adree Khondker
    Department of Physics and Astronomy, McMaster University, Hamilton ON L8S 4M1, Canada
  • Maikel C. Rheinstädter
    Maikel C. Rheinstädter
    Department of Physics and Astronomy, McMaster University, Hamilton ON L8S 4M1, Canada
  • Vincent Huynh
    Vincent Huynh
    Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada
  • Ryan G. Wylie
    Ryan G. Wylie
    Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada
  • José C. Bozelli Jr.
    José C. Bozelli, Jr.
    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton ON L8S 4M1, Canada
  • Richard M. Epand
    Richard M. Epand
    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton ON L8S 4M1, Canada
  • , and 
  • Giuseppe Melacini*
    Giuseppe Melacini
    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton ON L8S 4M1, Canada
    Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada
    *[email protected]
Cite this: J. Am. Chem. Soc. 2020, 142, 21, 9686–9699
Publication Date (Web):May 8, 2020
https://doi.org/10.1021/jacs.0c01894
Copyright © 2020 American Chemical Society

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    Abstract

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    Alpha synuclein (αS) oligomers are a key component of Lewy bodies implicated in Parkinson’s disease (PD). Although primarily intracellular, extracellular αS exocytosed from neurons also contributes to PD pathogenesis through a prion-like transmission mechanism. Here, we show at progressive degrees of resolution that the most abundantly expressed extracellular protein, human serum albumin (HSA), inhibits αS oligomer (αSn) toxicity through a three-pronged mechanism. First, endogenous HSA targets αSn with sub-μM affinity via solvent-exposed hydrophobic sites, breaking the catalytic cycle that promotes αS self-association. Second, HSA remodels αS oligomers and high-MW fibrils into chimeric intermediates with reduced toxicity. Third, HSA unexpectedly suppresses membrane interactions with the N-terminal and central αS regions. Overall, our findings suggest that the extracellular proteostasis network may regulate αS cell-to-cell transmission not only by reducing the populations of membrane-binding competent αS oligomers but possibly also by shielding the membrane interface from residual toxic species.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.0c01894.

    • ANS and Dan F binding sites in HSA, DARR controls, rHSA DEST profiles, HSQC and STDHSQC controls (PDF)

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    Cited By

    This article is cited by 8 publications.

    1. Jinfeng Huang, Rashik Ahmed, Madoka Akimoto, Karla Martinez Pomier, Giuseppe Melacini. Early-Onset Parkinson Mutation Remodels Monomer–Fibril Interactions to Allosterically Amplify Synuclein’s Amyloid Cascade. JACS Au 2023, 3 (12) , 3485-3493. https://doi.org/10.1021/jacsau.3c00655
    2. Sadhana Nirwal, Preethi Saravanan, Akarsh Bajpai, Vini D. Meshram, Gembali Raju, Waghela Deeksha, Ganesan Prabusankar, Basant K Patel. In Vitro Interaction of a C-Terminal Fragment of TDP-43 Protein with Human Serum Albumin Modulates Its Aggregation. The Journal of Physical Chemistry B 2022, 126 (45) , 9137-9151. https://doi.org/10.1021/acs.jpcb.2c04469
    3. Yangzhuoyue Jin, Gangjin Yu, Tairan Yuwen, Dawei Gao, Guan Wang, Yilin Zhou, Bin Jiang, Xu Zhang, Conggang Li, Lichun He, Maili Liu. Molecular Insight into the Extracellular Chaperone Serum Albumin in Modifying the Folding Free Energy Landscape of Client Proteins. The Journal of Physical Chemistry Letters 2022, 13 (12) , 2711-2717. https://doi.org/10.1021/acs.jpclett.2c00265
    4. Mengjuan Zhao, Cong Guo. Multipronged Regulatory Functions of Serum Albumin in Early Stages of Amyloid-β Aggregation. ACS Chemical Neuroscience 2021, 12 (13) , 2409-2420. https://doi.org/10.1021/acschemneuro.1c00150
    5. Rashik Ahmed, Jinfeng Huang, Madoka Akimoto, Tongyu Shi, Giuseppe Melacini. Atomic Resolution Map of Hierarchical Self-Assembly for an Amyloidogenic Protein Probed through Thermal 15N–R2 Correlation Matrices. Journal of the American Chemical Society 2021, 143 (12) , 4668-4679. https://doi.org/10.1021/jacs.0c13289
    6. Karla Martinez Pomier, Rashik Ahmed, Jinfeng Huang, Giuseppe Melacini. Inhibition of toxic metal-alpha synuclein interactions by human serum albumin. Chemical Science 2024, 137 https://doi.org/10.1039/D3SC06285F
    7. Carlos Navarro-Paya, Maximo Sanz-Hernandez, Alfonso De Simone. Plasticity of Membrane Binding by the Central Region of α-Synuclein. Frontiers in Molecular Biosciences 2022, 9 https://doi.org/10.3389/fmolb.2022.857217
    8. Karla Martinez Pomier, Rashik Ahmed, Giuseppe Melacini. Interactions of intrinsically disordered proteins with the unconventional chaperone human serum albumin: From mechanisms of amyloid inhibition to therapeutic opportunities. Biophysical Chemistry 2022, 282 , 106743. https://doi.org/10.1016/j.bpc.2021.106743

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