Study Rationale: The lysosome is a part of a cell involved in degrading and recycling proteins and other large molecules. Parkinson's disease (PD) is linked to lysosomal dysfunction. In this study, we focus on Atp6v0a1, a gene that maintains an acidic environment inside lysosomes. We will test if this gene is involved in PD-associated cell death. If so, it could provide a novel target for neuroprotection. We will determine whether modulating the levels of Atp6v0a1 can influence cell function in cell culture and laboratory models.
Hypothesis: We predict that reducing the activity of the lysosomal gene Atp6v0a1 will be neuroprotective in cell culture and in models of PD. We also predict that excessive Atp6v0a1 activation will be toxic.
Study Design: We will assess the impact of Atp6v0a1 inhibition and overexpression on cell function and survival. We will test in cultured neurons and in pre-clinical models of lysosomal stress and synucleinopathy.
Impact on Diagnosis/Treatment of Parkinson’s Disease: If Atp6v0a1 deficiency is neuroprotective, inhibiting this pathway could slow cell death in PD.
Next Steps for Development: Drug inhibitors of this pathway exist. Subsequent studies could therefore focus on testing and optimizing these inhibitors for neuroprotection in pre-clinical models of PD.