Study Rationale:
TMEM175 and ATP13A2 have been identified as risk genes for Parkinson’s disease. These proteins function to transport protons and polyamines through the lysosomal membrane to support organelle homeostasis, and these activities may be further regulated by the calcium channel TRPML1. Precisely how these proteins alter lysosomal health remains an open question whose answer may impact the development of therapeutics targeting these proteins.
Hypothesis:
We propose that understanding the biological consequences for loss of function of these proteins can facilitate their nomination as therapeutic targets, and such an understanding can also provide a platform for testing the biological activity of small molecule activators of these proteins.
Study Design:
We will use iPSC-derived neurons to profile cells and lysosomes lacking TRPML1, TMEM175 or ATP13A2 using a variety of assays that reveal lysosomal health, including alterations in the proteome and lipidome of lysosomes, measurement of channel activity in individual lysosomes, and polyamine flux within cells. We will also test and benchmark several candidate therapeutic molecules provided by biopharma using these assays. These efforts will be supported by creation of new sensors for polyamines as well as sensors for lysosomal damage/repair.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Several biopharma efforts are underway targeting TRPML1 and TMEM175, but bringing those molecules to patients will require additional data concerning the molecular effects of channel activation. This work will facilitate bringing such molecules to the clinic.
Next Steps for Development:
We expect that this study will create a foundation for expansion of biopharma activity in the search for molecules that increase the activity of lysosomes in PD by de-risking these targets.