Study Rationale:
LRRK2 is a protein regulated by kinases (protein regulators) and is also subject to autophosphorylation (auto-regulation). Several mutations of LRRK2 increase the kinase activity of the enzyme, thus LRRK2 inhibitors are potential preventative or disease-modifying drugs for Parkinon's disease (PD). There is considerable effort being put forward in the pharmaceutical industry towards designing and implementing pharmacological approaches to inhibit LRRK2 kinase activity. We have found that white blood cells from those with LRRK2-related PD have damage to their mitochondrial DNA (powerhouses of the cell; mtDNA). We will screen the ability of drugs that inhibit LRRK2 kinase activity to repair or fix mtDNA damage. We will also determine whether reversal of mtDNA damage is associated with altered LRRK2 activity.
Hypothesis:
Using our new therapeutic screening platform, we will test the hypothesis that reversal of
mtDNA damage in those with LRRK2-related PD correlates with inhibition of
LRRK2 kinase activity.
Study Design:
We will first determine whether drugs that inhibit LRRK2 can fix mtDNA damage in white blood cells from individuals with LRRK2-related PD. We will then test, under conditions that reverse mtDNA damage, whether LRRK2 kinase inhibitor treatment affects endogenous (within the body) LRRK2 activity.
Impact on Diagnosis/Treatment of Parkinson's Disease:
This study will allow us to determine whether the kinase activity of LRRK2 is a good target for reversing mtDNA damage. In the absence of reliable measures of target engagement of LRRK2 kinase inhibitors, mtDNA damage in an individual's own cells may prove useful to determine whether a treatment is reversing a relevant phenotype (i.e., a potential surrogate marker in the context of a clinical trial).
Next Steps for Development:
We have discovered increased levels of mtDNA damage in idiopathic (no known cause) PD. We would like to explore whether the pharmacological approach of LRRK2 kinase inhibition has utility beyond genetic (inherited) PD.