| Literature DB >> 27708076 |
Xiaobo Mao1, Michael Tianhao Ou2, Senthilkumar S Karuppagounder1, Tae-In Kam1, Xiling Yin1, Yulan Xiong1, Preston Ge2, George Essien Umanah1, Saurav Brahmachari1, Joo-Ho Shin3, Ho Chul Kang4, Jianmin Zhang2, Jinchong Xu1, Rong Chen1, Hyejin Park1, Shaida A Andrabi1, Sung Ung Kang1, Rafaella Araújo Gonçalves2, Yu Liang2, Shu Zhang2, Chen Qi5, Sharon Lam2, James A Keiler2, Joel Tyson6, Donghoon Kim2, Nikhil Panicker1, Seung Pil Yun1, Creg J Workman7, Dario A A Vignali8, Valina L Dawson9, Han Seok Ko10, Ted M Dawson11.
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.Entities:
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Year: 2016 PMID： 27708076 PMCID： PMC5510615 DOI： 10.1126/science.aah3374
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728