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

Mao XB; Ou MT; Karuppagounder SS; Kam TI; Yin XL; Xiong YL; Ge P; Umanah GE; Brahmachari S; Shin JH; Kang HC; Zhang JM; Xu JC; Chen R; Park H; Andrabi SA; Kang SU; Goncalves RA; Liang Y; Zhang S; Qi C; Lam SR; Keiler JA; Tyson J; Kim D; Panicker N; Yun SP; Workman CJ; Vignali DAA; Dawson VL; Ko HS; Dawso TM

Science, Vol.353, No.6307, 1513-1513, 2016

DOI10.1126/science.aah3374 Export Citation

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

Mao XB, Ou MT, Karuppagounder SS, Kam TI, Yin XL, Xiong YL, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang JM, Xu JC, Chen R, Park H, Andrabi SA, Kang SU, Goncalves RA, Liang Y, Zhang S, Qi C, Lam SR, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DAA, Dawson VL, Ko HS, Dawso TM

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