LRRK2-associated Mitochondrial DNA Damage as a Phenotype for Unbiased Screening

Objective/Rationale:  
The normal functions of LRRK2 are poorly understood, and the mechanism(s) by which LRRK2 mutations cause PD are unclear. Also, therapeutic development has been hampered by the lack of a robust, reproducible, quantitative phenotype for LRRK2 mutations (ie, there is no good ‘readout’ of what mutant LRRK2 does to neurons). We have found that neurons derived via induced pluripotent stem cells from LRRK2 PD patients have damage to their mitochondrial DNA (mtDNA). This appears to a reproducible readout of LRRK2 mutations, so we now propose to see if the same phenotype can be found in easily accessible tissues like skin cells (fibroblasts) or white blood cells (lymphoblasts). We will also test whether drugs that inhibit LRRK2 can ‘fix’ the phenotype.

Project Description:             
Aim 1 will determine whether fibroblasts (skin cells) or lymphoblasts (white blood cells) from people with LRRK2 mutations show the mtDNA damage phenotype. Assuming this is the case, Aim 2 will test whether drugs that inhibit LRRK2 (specific kinase inhibitors) can prevent or reverse the mtDNA damage.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Since scientists currently don’t have a firm understanding of how LRRK2 mutations cause PD, or of what the mutations do to cells to make them ‘sick’, it is hard to design or test drugs to block those effects. It is our hope that we will be able to provide a new way to screen novel therapies for those individuals with LRRK2 mutations.

Anticipated Outcome:          
Successful completion of this project will result in a new way to screen drugs to treat LRRK2-associated PD. Furthermore, it may provide a means of testing whether a drug is having the desired beneficial effect (reversing mtDNA damage) in patients who are being treated with drugs.