MT Keeney et al.
Parkinson’s Disease (PD) is a multifactorial disease that manifests from the complex interplay between aging, genetics and the environment; and the mechanisms underlying PD-associated neurodegeneration have yet to be fully elucidated.
Longstanding evidence implicates damage caused by oxidative stress as a major contributor to PD pathogenesis. Specifically, in the substantia nigra region of the brain of PD postmortem human tissue, there are increased amounts of the cell damaging byproducts of lipid and protein oxidation and diminished amounts of reduced glutathione, a key antioxidant that helps protect cells from excessive reactive oxygen species (ROS). Excessive ROS production and accumulation of lipid peroxidation products lead to protein damage and dysfunction, organelle impairment and ultimate cell death.
The substrates and downstream consequences of elevated LRRK2 kinase activity are still being evaluated, but overexpression of mutant LRRK2 has been associated with oxidative stress, and antioxidants have been shown to reduce LRRK2 related cellular toxicity.
This study found that elevated LRRK2 kinase activity was associated with increased ROS production and lipid peroxidation. Importantly, this damage was prevented by blocking either LRRK2 itself or another enzyme, NADPH oxidase 2 (NOX2), that generates ROS.
The pesticide rotenone triggered oxidative stress, but it was reduced by LRRK2 kinase inhibition and was not observed in cells without LRRK2. In a rat model of PD induced by rotenone, a LRRK2 kinase inhibitor prevented the lipid peroxidation and NOX2 activation that are normally seen in dopamine-producing neurons in this model.
Given the strong lipid peroxidation damage induced by LRRK2 kinase activity, this work suggests that oxidized lipid profiling could identify markers for therapeutic target engagement or treatment efficacy of LRRK2 or NOX2 inhibitors.
Additional information is available on the PubMed website: https://pubmed.ncbi.nlm.nih.gov/39356746/
