Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

Xiaobo Mao; Michael Tianhao Ou; Senthilkumar S. Karuppagounder; Tae In Kam; Xiling Yin; Yulan Xiong; Preston Ge; George Essien Umanah; Saurav Brahmachari; Joo Ho Shin; Ho Chul Kang; Jianmin Zhang; Jinchong Xu; Rong Chen; Hyejin Park; Shaida A. Andrabi; Sung Ung Kang; Rafaella Araújo Gonçalves; Yu Liang; Shu Zhang; Chen Qi; Sharon Lam; James A. Keiler; Joel Tyson; Donghoon Kim; Nikhil Panicker; Seung Pil Yun; Creg J. Workman; Dario A.A. Vignali; Valina L. Dawson; Han Seok Ko; Ted M. Dawson

doi:10.1126/science.aah3374

Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

Xiaobo Mao, Michael Tianhao Ou, Senthilkumar S. Karuppagounder, Tae In Kam, Xiling Yin, Yulan Xiong, Preston Ge, George Essien Umanah, Saurav Brahmachari, Joo Ho Shin, Ho Chul Kang, Jianmin Zhang, Jinchong Xu, Rong Chen, Hyejin Park, Shaida A. Andrabi, Sung Ung Kang, Rafaella Araújo Gonçalves, Yu Liang, Shu ZhangChen Qi, Sharon Lam, James A. Keiler, Joel Tyson, Donghoon Kim, Nikhil Panicker, Seung Pil Yun, Creg J. Workman, Dario A.A. Vignali, Valina L. Dawson, Han Seok Ko, Ted M. Dawson

School of Medicine

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

275 Scopus citations

Abstract

Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.

Original language	English (US)
Article number	aah3374
Journal	Science
Volume	353
Issue number	6307
DOIs	https://doi.org/10.1126/science.aah3374
State	Published - Sep 30 2016

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Mao, X., Ou, M. T., Karuppagounder, S. S., Kam, T. I., Yin, X., Xiong, Y., Ge, P., Umanah, G. E., Brahmachari, S., Shin, J. H., Kang, H. C., Zhang, J., Xu, J., Chen, R., Park, H., Andrabi, S. A., Kang, S. U., Gonçalves, R. A., Liang, Y., ... Dawson, T. M. (2016). Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science, 353(6307), Article aah3374. https://doi.org/10.1126/science.aah3374

Mao, X, Ou, MT, Karuppagounder, SS, Kam, TI, Yin, X, Xiong, Y, Ge, P, Umanah, GE, Brahmachari, S, Shin, JH, Kang, HC, Zhang, J, Xu, J, Chen, R, Park, H, Andrabi, SA, Kang, SU, Gonçalves, RA, Liang, Y, Zhang, S, Qi, C, Lam, S, Keiler, JA, Tyson, J, Kim, D, Panicker, N, Yun, SP, Workman, CJ, Vignali, DAA, Dawson, VL , Ko, HS & Dawson, TM 2016, 'Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3', Science, vol. 353, no. 6307, aah3374. https://doi.org/10.1126/science.aah3374

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title = "Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3",

abstract = "Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.",

author = "Xiaobo Mao and Ou, {Michael Tianhao} and Karuppagounder, {Senthilkumar S.} and Kam, {Tae In} and Xiling Yin and Yulan Xiong and Preston Ge and Umanah, {George Essien} and Saurav Brahmachari and Shin, {Joo Ho} and Kang, {Ho Chul} and Jianmin Zhang and Jinchong Xu and Rong Chen and Hyejin Park and Andrabi, {Shaida A.} and Kang, {Sung Ung} and Gon{\c c}alves, {Rafaella Ara{\'u}jo} and Yu Liang and Shu Zhang and Chen Qi and Sharon Lam and Keiler, {James A.} and Joel Tyson and Donghoon Kim and Nikhil Panicker and Yun, {Seung Pil} and Workman, {Creg J.} and Vignali, {Dario A.A.} and Dawson, {Valina L.} and Ko, {Han Seok} and Dawson, {Ted M.}",

year = "2016",

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doi = "10.1126/science.aah3374",

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AU - Mao, Xiaobo

AU - Ou, Michael Tianhao

AU - Karuppagounder, Senthilkumar S.

AU - Kam, Tae In

AU - Yin, Xiling

AU - Xiong, Yulan

AU - Ge, Preston

AU - Umanah, George Essien

AU - Brahmachari, Saurav

AU - Shin, Joo Ho

AU - Kang, Ho Chul

AU - Zhang, Jianmin

AU - Xu, Jinchong

AU - Chen, Rong

AU - Park, Hyejin

AU - Andrabi, Shaida A.

AU - Kang, Sung Ung

AU - Gonçalves, Rafaella Araújo

AU - Liang, Yu

AU - Zhang, Shu

AU - Qi, Chen

AU - Lam, Sharon

AU - Keiler, James A.

AU - Tyson, Joel

AU - Kim, Donghoon

AU - Panicker, Nikhil

AU - Yun, Seung Pil

AU - Workman, Creg J.

AU - Vignali, Dario A.A.

AU - Dawson, Valina L.

AU - Ko, Han Seok

AU - Dawson, Ted M.

PY - 2016/9/30

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N2 - Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.

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Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

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