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Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein

Author

Listed:
  • Xiaobo Mao

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Adrienne Helis Malvin Medical Research Foundation)

  • Hao Gu

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Nanjing Brain Hospital
    Yangzhou University)

  • Donghoon Kim

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Dong-A University)

  • Yasuyoshi Kimura

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Ning Wang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Enquan Xu

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Ramhari Kumbhar

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Adrienne Helis Malvin Medical Research Foundation)

  • Xiaotian Ming

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Haibo Wang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Chan Chen

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Sichuan University)

  • Shengnan Zhang

    (Chinese Academy of Sciences)

  • Chunyu Jia

    (Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Yuqing Liu

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Hetao Bian

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Senthilkumar S. Karuppagounder

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Fatih Akkentli

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Adrienne Helis Malvin Medical Research Foundation)

  • Qi Chen

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Longgang Jia

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Heehong Hwang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Su Hyun Lee

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Xiyu Ke

    (Johns Hopkins University
    Johns Hopkins University)

  • Michael Chang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Amanda Li

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Jun Yang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Cyrus Rastegar

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Manjari Sriparna

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Preston Ge

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Massachusetts Institute of Technology
    Picower Institute for Learning and Memory)

  • Saurav Brahmachari

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Sangjune Kim

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Chungbuk National University)

  • Shu Zhang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Yasushi Shimoda

    (Nagaoka University of Technology)

  • Martina Saar

    (University of Heidelberg)

  • Haiqing Liu

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Shandong First Medical University & Shandong Academy of Medical Sciences)

  • Sin Ho Kweon

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Mingyao Ying

    (Johns Hopkins University School of Medicine
    Hugo W. Moser Research Institute at Kennedy Krieger)

  • Creg J. Workman

    (University of Pittsburgh School of Medicine)

  • Dario A. A. Vignali

    (University of Pittsburgh School of Medicine
    UPMC Hillman Cancer Center)

  • Ulrike C. Muller

    (University of Heidelberg)

  • Cong Liu

    (Chinese Academy of Sciences)

  • Han Seok Ko

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Adrienne Helis Malvin Medical Research Foundation)

  • Valina L. Dawson

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Adrienne Helis Malvin Medical Research Foundation
    Johns Hopkins University School of Medicine)

  • Ted M. Dawson

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Adrienne Helis Malvin Medical Research Foundation
    Johns Hopkins University School of Medicine)

Abstract

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson’s disease and related α-synucleinopathies.

Suggested Citation

  • Xiaobo Mao & Hao Gu & Donghoon Kim & Yasuyoshi Kimura & Ning Wang & Enquan Xu & Ramhari Kumbhar & Xiaotian Ming & Haibo Wang & Chan Chen & Shengnan Zhang & Chunyu Jia & Yuqing Liu & Hetao Bian & Senth, 2024. "Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49016-3
    DOI: 10.1038/s41467-024-49016-3
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    References listed on IDEAS

    as
    1. Ed S. Lein & Michael J. Hawrylycz & Nancy Ao & Mikael Ayres & Amy Bensinger & Amy Bernard & Andrew F. Boe & Mark S. Boguski & Kevin S. Brockway & Emi J. Byrnes & Lin Chen & Li Chen & Tsuey-Ming Chen &, 2007. "Genome-wide atlas of gene expression in the adult mouse brain," Nature, Nature, vol. 445(7124), pages 168-176, January.
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