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

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.