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

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. Coordinated Lysosomal Expression and Regulation Glycoprotein non-metastatic melanoma protein B Microtubule-associated protein 1 light chain 3 Transient receptor potential mucolipin 1 We are very grateful to the Michael J. Fox Foundation for Parkinson’s Research (MJFF-025947) and The Silverstein Foundation who provided partial funding support for these studies.

Lysoway Therapeutics, Inc., 245 1st St, Ste 1800, Cambridge, MA, 02142, USA Valerie Cullen, Junsheng Yang, Xiang Yang Yu, Soheil Aghamohammadzadeh, Wanwan He, Chaoyue Zhang & Yongchang Qiu Neuro-Sys Vivo, SAS, 410 Chemin Départemental 60, 13120, Gardanne, France The authors declare the following competing interests: Valerie Cullen, Junsheng Yang, Xiang Yang Yu, Soheil Aghamohammadzadeh, Wanwan He, Xuliang Wang, Chaoyue Zhang, Shuqi Hang, and Yongchang Qiu are employees, shareholders, and/or former employees of Lysoway Therapeutics, which is developing LW-1017 and related lysosomal ion-channel modulators. Noelle Callizot and Alexandre Henriques are employees of Neuro-Sys Vivo, which performed the in vivo AD and PD pharmacology studies under contract with Lysoway Therapeutics. This work was funded by Lysoway Therapeutics, which was involved in study design, data interpretation, and the decision to submit the manuscript for publication.

All in vitro and in vivo target engagement studies were conducted at Hangzhou Rongwei Biotech Ltd. (Hangzhou, China) in accordance with applicable local laws and regulations governing animal research and with prior approval from the relevant institutional animal ethics committee. All in vivo pharmacology studies in Alzheimer’s disease and Parkinson’s disease mouse models were performed at Neuro-Sys SAS (410 Chemin Départemental 60, 13120 Gardanne, France) in compliance with French and European regulations for the use of animals in scientific research (Directive 2010/63/EU) and with approval from the appropriate local animal ethics committee. All procedures were performed by trained and authorized personnel in accredited facilities with appropriate animal welfare oversight.