The Human LRRK2-R1441G Mutation Drives Age-Dependent Oxidative Stress and Mitochondrial Dysfunction in Dopaminergic Neurons.

ABSTRACT: Mitochondrial dysfunction and oxidative stress are central to Parkinson's disease (PD) pathogenesis, particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in leucine-rich repeat kinase 2 (LRRK2), a key genetic contributor to familial and sporadic PD, impacts mitochondrial function in midbrain DA neurons. Using a BAC transgenic mouse model overexpressing human LRRK2-R1441G, we crossed these mice with TH-mito-roGFP mice, enabling mitochondria-targeted redox imaging in DA neurons. The two-photon imaging of acute brain slices from 3-, 6-, and 10-month-old mice revealed a progressive elevated oxidative stress in SNc DA neurons and their striatal projections, accompanied with reduced respiratory complex activity and declin

SUBMITTER: Chen Y 

PROVIDER: S-EPMC12262611 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature