The emergence of immune checkpoint pathways as central regulators of neurodegeneration has reshaped our understanding of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Among these, lymphocyte-activation gene 3 (LAG-3) has gained prominence not only as a classical immune checkpoint molecule but also as a neuronal receptor for pathogenic α-synuclein fibrils. This review proposes the novel hypothesis that LAG-3 functions as a dual-modulator in α-synucleinopathies facilitating the pathological spread of misfolded α-synuclein across neuronal networks while concurrently impairing neuroimmune clearance mechanisms via T cell exhaustion and microglial suppression. Recent studies have demonstrated that LAG-3 selectively binds α-synuclein fibrils, promoting their internalization and prion-like propagation in both experimental models and human post-mortem tissues. Simultaneously, LAG-3 expression on CNS-infiltrating and resident immune cells contributes to a suppressive immunological microenvironment, impairing phagocytosis and promoting disease progression. This dual role situates LAG-3 at a mechanistic crossroads between aggregate transmission and immune dysfunction. This review synthesizes emerging data on LAG-3’s structure, neuronal expression, immune interactions, and translational relevance, highlighting its potential as a therapeutic target and biomarker. Innovations in Nano body engineering, CNS-penetrant inhibitors, and multi-omic biomarker strategies are also discussed. By positioning LAG-3 as both a vector of propagation and a checkpoint of immune resilience, this paper offers a novel framework for rethinking targeted immunomodulation in neurodegenerative diseases.
Arpita Mukherjee (Mon,) studied this question.