[Research Article] Pathological ?-synuclein transmission initiated by binding lymphocyte-activation gene 3 (Science)

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 ?-synuclein (?-syn). The mechanism by which ?-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds ?-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the ?-syn monomer exhibited minimal binding. ?-Syn-biotin PFF binding to LAG3 initiated ?-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed ?-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 ?-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related ?-synucleinopathies. Authors: 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