Mao Xiaobo, Ou Michael Tianhao, Karuppagounder Senthilkumar S, Kam Tae-In, Yin Xiling, Xiong Yulan, Ge Preston, Umanah George Essien, Brahmachari Saurav, Shin Joo-Ho, Kang Ho Chul, Zhang Jianmin, Xu Jinchong, Chen Rong, Park Hyejin, Andrabi Shaida A, Kang Sung Ung, Gonçalves Rafaella Araújo, Liang Yu, Zhang Shu, Qi Chen, Lam Sharon, Keiler James A, Tyson Joel, Kim Donghoon, Panicker Nikhil, Yun Seung Pil, Workman Creg J, Vignali Dario A A, Dawson Valina L, Ko Han Seok, Dawson Ted M
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science. 2016 Sep 30;353(6307). doi: 10.1126/science.aah3374.
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.
新出现的证据表明，帕金森病（PD）的发病机制可能是由于α-突触核蛋白（α-syn）错误折叠的预制纤维（PFF）在细胞间的传播。α-syn PFF在神经元之间传播的机制尚不清楚。在这里，我们表明淋巴细胞激活基因3（LAG3）以高亲和力（解离常数=77纳摩尔）结合α-syn PFF，而α-syn单体的结合力最小。α-突触核蛋白-生物素PFF与LAG3的结合引发了α-syn PFF的内吞作用、传播和毒性。缺乏LAG3会显著延迟α-syn PFF诱导的多巴胺能神经元丧失以及体内的生化和行为缺陷。将LAG3鉴定为与α-syn PFF结合的受体，为开发旨在减缓PD和相关α-突触核蛋白病进展的治疗方法提供了一个靶点。
