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Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic α-synuclein

Xiaobo Mao, Hao Gu, Donghoon Kim, Yasuyoshi Kimura, Ning Wang, Enquan Xu, Haibo Wang, Chan Chen, Shengnan Zhang, Chunyu Jia, Yuqing Liu, Hetao Bian, Senthilkumar S. Karuppagounder, Longgang Jia, Xiyu Ke, Michael Chang, Amanda Li, Jun Yang, Cyrus Rastegar, Manjari Sriparna, Preston Ge, Saurav Brahmachari, Sangjune Kim, Shu Zhang, Yasushi Shimoda, Martina Saar, Creg J. Workman, Dario A. A. Vignali, Ulrike C. Muller, Cong Liu, Han Seok Ko, Valina L. Dawson, Ted M. Dawson
doi: https://doi.org/10.1101/2021.05.01.442157
Xiaobo Mao
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
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  • For correspondence: tdawson@jhmi.edu vdawson1@jhmi.edu xmao4@jhmi.edu hko3@jhmi.edu
Hao Gu
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Donghoon Kim
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Yasuyoshi Kimura
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Ning Wang
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Enquan Xu
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Haibo Wang
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Chan Chen
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Shengnan Zhang
4Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai 201210, China
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Chunyu Jia
4Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai 201210, China
5University of the Chinese Academy of Sciences, 19 A Yuquan Road, Shijingshan District, Beijing 100049, China
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Yuqing Liu
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Hetao Bian
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Senthilkumar S. Karuppagounder
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Longgang Jia
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Xiyu Ke
6Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
7Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
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Michael Chang
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Amanda Li
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Jun Yang
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Cyrus Rastegar
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Manjari Sriparna
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Preston Ge
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Saurav Brahmachari
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Sangjune Kim
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Shu Zhang
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Yasushi Shimoda
8Department of Bioengineering, Nagaoka University of Technology, 1603-1 Kamitomiokamachi, Nagaoka, Niigata, 940-2188 Japan
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Martina Saar
9Institute for Pharmacy and Molecular Biotechnology IPMB, Department of Functional Genomics, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg
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Creg J. Workman
10Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Dario A. A. Vignali
10Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
11Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
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Ulrike C. Muller
9Institute for Pharmacy and Molecular Biotechnology IPMB, Department of Functional Genomics, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg
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Cong Liu
4Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai 201210, China
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Han Seok Ko
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
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  • For correspondence: tdawson@jhmi.edu vdawson1@jhmi.edu xmao4@jhmi.edu hko3@jhmi.edu
Valina L. Dawson
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
12Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
13Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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  • For correspondence: tdawson@jhmi.edu vdawson1@jhmi.edu xmao4@jhmi.edu hko3@jhmi.edu
Ted M. Dawson
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
13Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
14Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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  • For correspondence: tdawson@jhmi.edu vdawson1@jhmi.edu xmao4@jhmi.edu hko3@jhmi.edu
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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) forms a complex 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 advances our understanding of the molecular mechanism 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.

One Sentence Summary Aplp1 forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-synuclein.

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Aplp1 and the Aplp1-Lag3 complex facilitates transmission of pathologic α-synuclein.

Aplp1 is a receptor that drives pathologic α-syn transmission, and genetic depletion of Aplp1 can significantly reduce the α-synuclein pathogenesis. Aplp1 and Lag3 forms an Aplp1-Lag3 complex that accounts for substantial binding of pathologic α-syn to cortical neurons. Together Aplp1 and Lag3 play a major role in pathologic α-syn internalization, transmission and toxicity. Double knockout of Aplp1 and Lag3 and or a Lag3 antibody that disrupts the Aplp1 and Lag3 complex almost completely blocks α-syn PFF-induced neurodegeneration.

Competing Interest Statement

DAAV and CJW have submitted patents on Lag3 that are approved or pending and are entitled to a share in net income generated from licensing of these patent rights for commercial development.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted May 01, 2021.
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Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic α-synuclein
Xiaobo Mao, Hao Gu, Donghoon Kim, Yasuyoshi Kimura, Ning Wang, Enquan Xu, Haibo Wang, Chan Chen, Shengnan Zhang, Chunyu Jia, Yuqing Liu, Hetao Bian, Senthilkumar S. Karuppagounder, Longgang Jia, Xiyu Ke, Michael Chang, Amanda Li, Jun Yang, Cyrus Rastegar, Manjari Sriparna, Preston Ge, Saurav Brahmachari, Sangjune Kim, Shu Zhang, Yasushi Shimoda, Martina Saar, Creg J. Workman, Dario A. A. Vignali, Ulrike C. Muller, Cong Liu, Han Seok Ko, Valina L. Dawson, Ted M. Dawson
bioRxiv 2021.05.01.442157; doi: https://doi.org/10.1101/2021.05.01.442157
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Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic α-synuclein
Xiaobo Mao, Hao Gu, Donghoon Kim, Yasuyoshi Kimura, Ning Wang, Enquan Xu, Haibo Wang, Chan Chen, Shengnan Zhang, Chunyu Jia, Yuqing Liu, Hetao Bian, Senthilkumar S. Karuppagounder, Longgang Jia, Xiyu Ke, Michael Chang, Amanda Li, Jun Yang, Cyrus Rastegar, Manjari Sriparna, Preston Ge, Saurav Brahmachari, Sangjune Kim, Shu Zhang, Yasushi Shimoda, Martina Saar, Creg J. Workman, Dario A. A. Vignali, Ulrike C. Muller, Cong Liu, Han Seok Ko, Valina L. Dawson, Ted M. Dawson
bioRxiv 2021.05.01.442157; doi: https://doi.org/10.1101/2021.05.01.442157

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