Neuronal LAG3 facilitates pathogenic α-synuclein neuron-to-neuron propagation

Lymphocyte activation gene 3 (LAG3) is a key receptor involved in the propagation of pathological proteins in Parkinson’s disease (PD). This study investigates the role of neuronal LAG3 in mediating the binding, uptake, and propagation of α-synuclein (αSyn) preformed fibrils (PFFs). Using neuronal LAG3 conditional knockout mice and human induced pluripotent stem cells-derived dopaminergic (DA) neurons, we demonstrate that LAG3 expression is critical for pathogenic αSyn propagation. Our results show that the absence of neuronal LAG3 significantly reduces αSyn pathology, alleviates motor dysfunction, and inhibits neurodegeneration in vivo . Electrophysiological recordings revealed that αSyn PFFs induce pronounced neuronal hyperactivity in wild-type (WT) neurons, increasing firing rates in cell-attached and whole-cell configurations, and reducing miniature excitatory postsynaptic currents. In contrast, neurons lacking LAG3 resisted these electrophysiological effects. Moreover, treatment with an anti-human LAG3 antibody in human DA neurons inhibited αSyn PFFs binding and uptake, preventing pathology propagation. These findings confirm the essential function of neuronal LAG3 in mediating αSyn propagation and associated disruptions, identifying LAG3 as a potential therapeutic target for PD and related α-synucleinopathies.