Nature Communications (May 2024)
Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein
- 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,
- Senthilkumar S. Karuppagounder,
- Fatih Akkentli,
- Qi Chen,
- Longgang Jia,
- Heehong Hwang,
- Su Hyun Lee,
- Xiyu Ke,
- Michael Chang,
- Amanda Li,
- Jun Yang,
- Cyrus Rastegar,
- Manjari Sriparna,
- Preston Ge,
- Saurav Brahmachari,
- Sangjune Kim,
- Shu Zhang,
- Yasushi Shimoda,
- Martina Saar,
- Haiqing Liu,
- Sin Ho Kweon,
- Mingyao Ying,
- Creg J. Workman,
- Dario A. A. Vignali,
- Ulrike C. Muller,
- Cong Liu,
- Han Seok Ko,
- Valina L. Dawson,
- Ted M. Dawson
Affiliations
- Xiaobo Mao
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Hao Gu
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Donghoon Kim
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Yasuyoshi Kimura
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Ning Wang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Enquan Xu
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Ramhari Kumbhar
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Xiaotian Ming
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Haibo Wang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Chan Chen
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Shengnan Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Chunyu Jia
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Yuqing Liu
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Hetao Bian
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Senthilkumar S. Karuppagounder
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Fatih Akkentli
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Qi Chen
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Longgang Jia
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Heehong Hwang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Su Hyun Lee
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Xiyu Ke
- Institute for NanoBioTechnology, Johns Hopkins University
- Michael Chang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Amanda Li
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Jun Yang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Cyrus Rastegar
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Manjari Sriparna
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Preston Ge
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Saurav Brahmachari
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Sangjune Kim
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Shu Zhang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Yasushi Shimoda
- Department of Bioengineering, Nagaoka University of Technology
- Martina Saar
- Institute for Pharmacy and Molecular Biotechnology IPMB, Department of Functional Genomics, University of Heidelberg
- Haiqing Liu
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Sin Ho Kweon
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Mingyao Ying
- Department of Neurology, Johns Hopkins University School of Medicine
- Creg J. Workman
- Department of Immunology, University of Pittsburgh School of Medicine
- Dario A. A. Vignali
- Department of Immunology, University of Pittsburgh School of Medicine
- Ulrike C. Muller
- Institute for Pharmacy and Molecular Biotechnology IPMB, Department of Functional Genomics, University of Heidelberg
- Cong Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Han Seok Ko
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Valina L. Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- Ted M. Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
- DOI
- https://doi.org/10.1038/s41467-024-49016-3
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 19
Abstract
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.
