A brain-penetrant TRPML1 agonist enhances autophagy–lysosomal function and mitigates pathology in aged models of Parkinson’s and Alzheimer’s diseases

Abstract Age-related decline in autophagy–lysosomal pathway function is a key contributor to the accumulation of toxic protein aggregates, neuroinflammation, and neuronal loss in neurodegenerative diseases. Transient receptor potential mucolipin-1 (TRPML1) is a lysosomal Ca²⁺ channel that coordinates acute lysosomal signaling and MiT/TFE-dependent transcription to promote lysosomal biogenesis, cellular clearance, and neuronal resilience. Despite strong mechanistic rationale, whether pharmacological activation of TRPML1 can therapeutically modulate disease-relevant pathology in vivo has remained unresolved. Here, we describe LW-1017, a potent, selective, and brain-penetrant small-molecule TRPML1 agonist and evaluate its pharmacodynamic activity and therapeutic effects in aged preclinical mouse models of Parkinson’s disease (PD) and Alzheimer’s disease (AD). LW-1017 activated TRPML1-mediated ion conductance and induced concentration-dependent nuclear translocation of TFEB/TFE3/MiTF, leading to coordinated activation of CLEAR network genes. In vivo, oral administration achieved robust central nervous system exposure and produced sustained modulation of lysosomal and autophagy biomarkers, including lipidation of LC3 and GABARAPL1 and induction of lysosome-associated proteins. In an aged α-synuclein–based PD model, LW-1017 dose-dependently reduced pathological α-synuclein, attenuated gliosis, preserved nigrostriatal dopaminergic integrity, and improved motor performance. In an aged amyloid-β oligomer model of AD, LW-1017 reduced amyloid and phosphorylated tau pathology, decreased neuroinflammation, preserved neuronal integrity, and improved cognition. Efficacy was observed at low oral doses (3 mg/kg/day), consistent with efficient brain penetration and target engagement. Together, these findings provide the first in vivo evidence that pharmacological activation of TRPML1 can engage autophagy–lysosomal pathways and ameliorate pathology in aged models of both AD and PD, supporting TRPML1 agonism as a promising strategy to counteract age-associated neurodegenerative disease.