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

doi:10.1038/s41467-024-49016-3

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 LeeXiyu 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	4663
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-49016-3
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Mao, X., Gu, H., Kim, D., Kimura, Y., Wang, N., Xu, E., Kumbhar, R., Ming, X., Wang, H., Chen, C., Zhang, S., Jia, C., Liu, Y., Bian, H., Karuppagounder, S. S., Akkentli, F., Chen, Q., Jia, L., Hwang, H., ... Dawson, T. M. (2024). Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein. Nature communications, 15(1), Article 4663. https://doi.org/10.1038/s41467-024-49016-3

Mao, X, Gu, H, Kim, D, Kimura, Y, Wang, N, Xu, E, Kumbhar, R, Ming, X, Wang, H, Chen, C, Zhang, S, Jia, C, Liu, Y, Bian, H, Karuppagounder, SS, Akkentli, F, Chen, Q, Jia, L, Hwang, H, Lee, SH, Ke, X, Chang, M, Li, A, Yang, J, Rastegar, C, Sriparna, M, Ge, P, Brahmachari, S, Kim, S, Zhang, S, Shimoda, Y, Saar, M, Liu, H, Kweon, SH , Ying, M, Workman, CJ, Vignali, DAA, Muller, UC, Liu, C, Ko, HS , Dawson, VL & Dawson, TM 2024, 'Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein', Nature communications, vol. 15, no. 1, 4663. https://doi.org/10.1038/s41467-024-49016-3

@article{0bcf9a00af784894bf1180c5c8fa9f15,

title = "Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein",

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{\textquoteright}s disease and related α-synucleinopathies.",

author = "Xiaobo Mao and Hao Gu and Donghoon Kim and Yasuyoshi Kimura and Ning Wang and Enquan Xu and Ramhari Kumbhar and Xiaotian Ming and Haibo Wang and Chan Chen and Shengnan Zhang and Chunyu Jia and Yuqing Liu and Hetao Bian and Karuppagounder, {Senthilkumar S.} and Fatih Akkentli and Qi Chen and Longgang Jia and Heehong Hwang and Lee, {Su Hyun} and Xiyu Ke and Michael Chang and Amanda Li and Jun Yang and Cyrus Rastegar and Manjari Sriparna and Preston Ge and Saurav Brahmachari and Sangjune Kim and Shu Zhang and Yasushi Shimoda and Martina Saar and Haiqing Liu and Kweon, {Sin Ho} and Mingyao Ying and Workman, {Creg J.} and Vignali, {Dario A.A.} and Muller, {Ulrike C.} and Cong Liu and Ko, {Han Seok} and Dawson, {Valina L.} and Dawson, {Ted M.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-49016-3",

language = "English (US)",

volume = "15",

journal = "Nature communications",

issn = "2041-1723",

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number = "1",

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TY - JOUR

T1 - Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein

AU - Mao, Xiaobo

AU - Gu, Hao

AU - Kim, Donghoon

AU - Kimura, Yasuyoshi

AU - Wang, Ning

AU - Xu, Enquan

AU - Kumbhar, Ramhari

AU - Ming, Xiaotian

AU - Wang, Haibo

AU - Chen, Chan

AU - Zhang, Shengnan

AU - Jia, Chunyu

AU - Liu, Yuqing

AU - Bian, Hetao

AU - Karuppagounder, Senthilkumar S.

AU - Akkentli, Fatih

AU - Chen, Qi

AU - Jia, Longgang

AU - Hwang, Heehong

AU - Lee, Su Hyun

AU - Ke, Xiyu

AU - Chang, Michael

AU - Li, Amanda

AU - Yang, Jun

AU - Rastegar, Cyrus

AU - Sriparna, Manjari

AU - Ge, Preston

AU - Brahmachari, Saurav

AU - Kim, Sangjune

AU - Zhang, Shu

AU - Shimoda, Yasushi

AU - Saar, Martina

AU - Liu, Haiqing

AU - Kweon, Sin Ho

AU - Ying, Mingyao

AU - Workman, Creg J.

AU - Vignali, Dario A.A.

AU - Muller, Ulrike C.

AU - Liu, Cong

AU - Ko, Han Seok

AU - Dawson, Valina L.

AU - Dawson, Ted M.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-024-49016-3

DO - 10.1038/s41467-024-49016-3

M3 - Article

C2 - 38821932

AN - SCOPUS:85195006289

SN - 2041-1723

VL - 15

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4663

ER -

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

Abstract

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