Funded Studies
Study Rationale:
People with Parkinson’s disease (PD) exhibit a diminished ability to remove cellular trash — including old and damaged molecules and organelles — from the brain. This impairment is caused by a reduction in trash collection and delivery (a process called macroautophagy) and a decline in the number and effectiveness of trash cans (compartments called lysosomes). Activation of TRPML1, a channel that resides on the lysosome, has been shown to enhance macroautophagy and to increase lysosome function and number in cells. Therapeutics that boost TRPML1 activity could therefore alleviate the symptoms and progression of PD.
Hypothesis:
We hypothesize that developing small compounds that can activate TRPML1 should also enhance macroautophagy and increase lysosome function in animals and potentially in humans.
Study Design:
In this project, we seek to demonstrate that activation of TRPML1 increases macroautophagy and lysosome growth signaling in animals, and that this activation and its subsequent effects are dose dependent. We will then determine whether and how much activation of TRPML1 is needed to show beneficial effects in animal models of PD. Lastly, we seek to lay the foundation for development of an assay or suite of assays that will allow us to measure activation of TRPML1 and its subsequent activation of macroautophagy and lysosome growth signaling in future clinical trials.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Establishing that activation of TRPML1 increases macroautophagy and lysosome growth signaling in animals, and that these effects can be monitored in potential future clinical trials, would provide a strong body of evidence supporting the development of small compounds that can activate TRPML1 for the treatment of PD.
Next Steps for Development:
Success in this grant would provide strong support for the continued advancement of Libra’s small compound TRPML1 activators into animal toxicology studies, which are required for advancement into clinical safety evaluation in people with PD and healthy volunteers.
Additional Support:
The Michael J. Fox Foundation would like to acknowledge the generous contribution of the Demoucelle Parkinson Charity as a lead supporter providing funding for this project.