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

Authors

• Yuanxin Chen, Thomas Jefferson UniversityFollow
• Lianteng Zhi, Thomas Jefferson University
• Shiquan Cui
• Huaixin Wang, Thomas Jefferson University
• Chenbo Zeng, Thomas Jefferson UniversityFollow
• Hui Zhang

Document Type

Article

Publication Date

7-7-2026

Comments

This article is the author’s final published version in Molecular Neurodegeneration, Volume 21, July 2026, Article number 69.

The published version is available at https://doi.org/10.1186/s13024-026-00969-7. Copyright © The Author(s) 2026.

Abstract

BACKGROUND: Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of Parkinson's disease (PD), 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.

METHODS: We employed a BAC transgenic mouse model overexpressing human LRRK2-R1441G (BAC-hR1441G) and crossed it with TH-mito-roGFP mice to enable mitochondria-targeted redox imaging specifically in DA neurons. Acute midbrain slices from 3-, 6-, and 12-month-old mice were imaged using two-photon microscopy to assess mitochondrial oxidative stress. In parallel, mitochondrial respiratory function, membrane potential flickering events, and expression of uncoupling proteins (UCP4/UCP5) were analyzed. Spatial transcriptomic profiling was performed using the GeoMx® Digital Spatial Profiler to uncover associated molecular alterations.

RESULTS: We observed a progressive increase in mitochondrial oxidative stress in SNc DA neurons of BAC-hR1441G mice at 3, 6, and 12 months of age. This was accompanied by reduced respiratory complex activity, attenuated mitochondrial membrane potential flickering, and diminished expression of UCP4 and UCP5. Spatial transcriptomic analysis revealed dysregulation of genes linked to mitochondrial uncoupling, calcium signaling, and redox regulation in BAC-hR1441G SNc DA neurons.

CONCLUSIONS: These findings reveal an age-dependent progression of mitochondrial dysfunction in BAC-hR1441G SNc DA neurons. Dysregulation of calcium channels and uncoupling proteins emerges as a key mechanism contributing to bioenergetic failure, suggesting potential therapeutic targets to mitigate PD progression.

Recommended Citation

Chen, Yuanxin; Zhi, Lianteng; Cui, Shiquan; Wang, Huaixin; Zeng, Chenbo; and Zhang, Hui, "The Human LRRK2-R1441G Mutation Drives Age-Dependent Oxidative Stress and Mitochondrial Dysfunction in Dopaminergic Neurons" (2026). Department of Neuroscience Faculty Papers. Paper 98.
https://jdc.jefferson.edu/department_neuroscience/98

Language

English