Study Rationale:
One of the most common inherited causes of Parkinson’s disease (PD) is defect in the LRRK2 protein caused by changes, or mutations, of the LRRK2 gene. These LRRK2 mutations cause the LRRK2 protein to become overactive, which is believed to damage brain cells and interfere with the process of dopamine release from the cells in PD. Thus, hyperactive LRRK2 represents a therapeutic target in inherited PD. Potent drugs that deactivate LRRK2 exist, but their safety and therapeutic efficacy has not been confirmed. Given the ability of these drug candidates to interfere with cells’ energy supply, alternative therapeutics with a different mechanism of action should be considered. We have identified a vitamin that can deactivate LRRK2 without unwanted side effects.
Hypothesis:
We hypothesize that the vitamin could become a new therapy for inherited LRRK2 mutation–linked PD.
Study Design:
We aim to understand how the vitamin deactivates the LRRK2 protein (Aim 1) and protects the brain when LRRK2 is overactive (Aim 2). Working toward Aim 1, we will examine how the vitamin interacts with and deactivates the LRRK2 protein. Working toward Aim 2, we will investigate how the vitamin prevents the death of neural cells with overactive LRRK2 in vitro. Finally, we will assess the ability of the vitamin to improve dopamine release in pre-clinical models of PD with LRRK2 mutations.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Our study will characterize a new type of LRRK2 deactivating agent with a distinct mechanism of action. Our findings will support further development of the vitamin or similar agents into future therapeutics for PD.
Next Steps for Development:
Next, we will evaluate in pre-clinical and clinical studies the safety of the vitamin and similar agents and their efficacy in blocking LRRK2-mediated toxicity.