Study Rationale:
Lysosomes are small compartments that function as the garbage disposal of the cells, eliminating toxic accumulations. Malfunction of these organelles impact the clearance of waste materials and cause a variety of diseases. Multiple forms of Parkinson’s disease (PD) are linked to lysosomal dysfunction. The most common genetic risk factor for Parkinson’s is a change in the GBA gene, which encodes the protein glucocerebrosidase (GCase). GCase functions inside lysosomes to breakdown fatty substances called lipids. Recent experiments have shown that activation of the lysosomal ion channel TRPML1 can fix malfunctions in various cellular models of lysosomal dysfunction.
Hypothesis:
We hypothesize that increasing TRPML1 activity with a drug-like small molecule will improve health and function in cells derived from PD patients with a GBA mutation.
Study Design:
We will create new activators of TRMPL1 then test these compounds and select the best ones to test on cells derived from human patients, to see if they improve the function and health of those cells.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If successful, this will validate a new druggable, cellular target for PD treatment.
Next Steps for Development:
We plan to embark on a full-scale drug discovery effort to develop a novel, orally administered therapeutic for the treatment of Parkinson’s disease associated with GBA dysfunction. Recent studies suggest GBA dysfunction may be present in a sizeable group of idiopathic PD patients, so we will also explore that possibility.