Study Rationale: The protein TRPML1 regulates the clearance of cellular debris, including aggregated alpha-synuclein and toxic lipids—a process that is disrupted in Parkinson’s disease (PD). We have identified molecules that activate TRPML1 and have therapeutic potential for the treatment of PD. In previous work, we have shown that these compounds can alter the production of toxic lipids and the processing of alpha-synuclein in neurons derived from people with GBA-associated PD. Now, we seek to further evaluate these processes as potential biomarkers for in future clinical trials of TRPML1 activators.
Hypothesis: Based on prior work in neurons derived from people with PD, we predict that activation of TRPML1 will alter the levels of alpha-synuclein and certain membrane-based lipids. We also predict that these changes could serve as biomarkers for clinical trials of compounds that stimulate TRPML1.
Study Design: We will treat isolated neurons with compounds that activate TRPML1 and monitor changes in alpha-synuclein processing. We will also determine how these activators affect the levels of PD-associated lipids and proteins in preclinical models of PD and in animals that do not display PD pathology.
Impact on Diagnosis/Treatment of Parkinson’s disease: The development of robust biomarkers will support determination of effective dosages and selection of individuals most likely to benefit in clinical trials of TRPML1 activators in people with GBA-associated PD. The same biomarkers will also facilitate studies of how TRPML1 activators affect disease processes.
Next Steps for Development: The next step would be to select a compound with drug-like properties and perform the studies needed to test its potential in people with PD. To support this program, we will develop protocols that facilitate accurate measurement of biomarkers that change in response to TRPML1 activation in a clinical context.