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

Study Rationale:
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.

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.

Study Design:
We found that ATP13A2 contains an auto-inhibitory domain that can be targeted for activation. To identify ATP13A2 agonists that target this domain, we plan a complete screen-to-hit and hit characterization program. High-throughput screening will be performed on purified human ATP13A2. Confirmation and specificity of the hits will be analyzed via various orthogonal biochemical assays, and their impact on the transport function of ATP13A2 will be assessed. A minimum of two hit series will be selected with favorable drug-like properties, robust potency (< 1 µM) and selectivity on ATP13A2. It will be tested whether these compounds enhance lysosomal function and confer mitochondrial protection in available cell models of ATP13A2.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
ATP13A2 agonists will serve as essential tools for the validation of ATP13A2 as a therapeutic PD target. We predict that ATP13A2 agonists will slow down or halt PD progression by rescuing lysosomal and mitochondrial dysfunction, thereby targeting key hallmarks of PD.

Next Steps for Development:
Strong hit series at the end of this program will enter hit-to-lead development and lead optimization. Via medicinal chemistry, we will enhance potency, selectivity and drug-like features of the compounds, and validate lead compounds in vivo in PD models. The goal of our program is to deliver a pre-clinical drug candidate that can enter clinical trials.


Additional Support:
The Michael J. Fox Foundation would like to acknowledge the generous contribution of the Demoucelle Parkinson Charity as a lead supporter providing funding for this phase of the project.


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