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

Academic Article

Abstract

  • © 2016, American Association for the Advancement of Science. All rights reserved. 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.
  • Published In

  • Science  Journal
  • Digital Object Identifier (doi)

    Author List

  • Mao X; Ou MT; Karuppagounder SS; Kam TI; Yin X; Xiong Y; Ge P; Umanah GE; Brahmachari S; Shin JH
  • Volume

  • 353
  • Issue

  • 6307