Nicholas Pena et al.
In this study, researchers used 4 NINDS Repository lymphoblastoid cell lines (LCLs) to study Parkinson’s disease (PD). These lines consisted of two PD patient cell lines with a G2019S LRRK2 mutation and two healthy controls. Pathogenic mutations in LRRK2 cause PD. The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. In a previous study, the researchers demonstrated that mitochondrial DNA (mtDNA) damage in human heterozygous G2019S LRRK2 PD patient-derived cells was restored to healthy control levels following treatment with LRRK2 kinase inhibitors. In the current study, researchers tested two different inhibitors: a selective one, called EB-42168, and a non-selective one, called MLi-2. EB-42168 reduced the mtDNA damage only in cells with G2019S LRRK2 mutations, suggesting that it may serve as a safer and more specific option. Even though the inhibitors were able to reduce mtDNA damage, they did not have an effect on mitophagy (a process of removing damaged mitochondria from the cell), suggesting that mitophagy is not mechanistically regulating LRRK2 kinase-mediated reversal of mtDNA damage. Together, these data indicate that a targeted LRRK2 inhibitor, such as EB-42168, could safely reduce harmful enzyme activity from the G2019S mutation in Parkinson’s patients, without affecting healthy cells. Monitoring mtDNA damage could also be a helpful biomarker in clinical trials, supporting the development of improved Parkinson’s therapies.
Additional information is available on the PubMed website:
PMID: 38429321
