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

Science. 2016 Sep 30;353(6307):aah3374. doi: 10.1126/science.aah3374.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Dopaminergic Neurons / metabolism
  • Endocytosis
  • Humans
  • Lymphocyte Activation Gene 3 Protein
  • Mice
  • Mice, Transgenic
  • Parkinson Disease / metabolism*
  • Protein Binding
  • Protein Transport
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Antigens, CD
  • SNCA protein, human
  • alpha-Synuclein
  • Lymphocyte Activation Gene 3 Protein