LAMP2A gene therapy mitigates Parkinson's disease-related pathology in nonhuman primates

Chaperone-mediated autophagy (CMA), regulated by its lysosomal receptor LAMP2A, is a key pathway for αSynuclein (αSyn) clearance and a direct target of αSyn-related neurotoxicity. Rodent studies show that LAMP2A enhancement reverses neurodegeneration, whereas its deficiency accelerates pathology. To test translational relevance, we examined whether increasing LAMP2A expression in nonhuman primates could mitigate α-synucleinopathy induced by injections of Parkinson's disease patient-derived Lewy body (LB) extract. Increasing LAMP2A expression protected nigral dopaminergic neurons from LB-induced αSyn neurodegeneration, delayed the formation and release of pathology-related αSyn species, and evoked a beneficial effect on motor behavior and on cognitive functions of the primate model. Our findings provide preliminary preclinical evidence supporting CMA enhancement as a therapeutic strategy for αSynucleinopathies.