Identification and Characterization of Small Molecule Activators of ATP13A2 for Parkinson’s Disease Therapy (MJFF ATP13A2)

In Parkinson’s disease, neurons degenerate because of a disturbed function of the lysosomes and mitochondria. The lysosomal transporter ATP13A2 (PARK9) is genetically implicated in familial forms of Parkinson’s disease and may represent an interesting drug target to restore these problems. We discovered that ATP13A2 transports a substrate that provides an antioxidant function and counteracts oxidative stress as a result of mitochondrial damage. Moreover, a disturbed ATP13A2 function leads to accumulation of substrates in the lysosome, which is toxic and causes lysosomal dysfunction and cell death. Together, ATP13A2 provides a potent neuroprotective effect at the level of the mitochondria and lysosomes.

Hypothesis:
We hypothesize that ATP13A2 agonists may be a novel and attractive neuroprotective strategy for improving lysosomal functionality and lowering oxidative stress, which may prevent neurodegeneration and be used for Parkinson’s disease (PD) therapy.