Xiaobo Mao1,2,3, Michael Tianhao Ou1,2, Senthilkumar S. Karuppagounder1,2,3, Tae-In Kam1,2,3, Xiling Yin1,2,3, Yulan Xiong1,2,3,*, Preston Ge1,2, George Essien Umanah1,2,3, Saurav Brahmachari1,2,3, Joo-Ho Shin1,2,4, Ho Chul Kang1,2,5, Jianmin Zhang1,2,†, Jinchong Xu1,2,3, Rong Chen1,2,3, Hyejin Park1,2,3, Shaida A. Andrabi1,2,3,‡, Sung Ung Kang1,2,3, Rafaella Araujo Goncalves1,2,§, Yu Liang1,2, Shu Zhang1,2, Chen Qi1,2,6, Sharon Lam1,2, James A. Keiler1,2, Joel Tyson1,2,7, Donghoon Kim1,2, Nikhil Panicker1,2,3, Seung Pil Yun1,2,3, Creg J. Workman8, Dario A. A. Vignali8,9, Valina L. Dawson1,2,3,10,11,||, Han Seok Ko1,2,3,||, Ted M. Dawson1,2,7,11,12,||
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.
4Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea.
5Department of Physiology, Ajou University School of Medicine, Suwon 443-721, South Korea.
6Department of Neurology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
7Johns Hopkins Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA.
8Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
9Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
10Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
||Corresponding author. Ted M. Dawson; Han Seok Ko; Valina L. Dawson
* Present address: Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA.
† Present address: State Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
‡ Present address: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
§ Present address: Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
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.