Antioxidant PRDX3 gene therapy protects brain cells and prevents neurodegeneration in an animal model of Parkinson's disease

Abstract

Neurodegenerative diseases, including Parkinson's Disease (PD), are a significant global health challenge with no effective therapies to counteract neurodegeneration. Genetic and environmental factors lead to mitochondrial dysfunction and increased reactive oxygen species (ROS), resulting in oxidative stress. This stress reduces levels of Peroxiredoxin 3 (PRDX3), a key protein for maintaining ROS balance at the mitochondrial level, increasing the substantia nigra's susceptibility to damage. To investigate the protective role of antioxidant gene therapy in a PD model, we overexpressed the PRDX3 enzyme using a cell-penetrating peptide-based delivery system (mRVG9R-PRDX3 complex). The mRVG9R peptide was combined with a green fluorescent protein (GFP) reporter plasmid expressing PRDX3 to create the complex. Overexpression of the PRDX3 gene in neuronal phenotype cells was confirmed in vitro using dopaminergic SH-SY5Y cells. Following successful in vitro expression, the mRVG9R-PRDX3 complex was stereotaxically injected into the striatum of male C57BL/6 mice. The PD model was induced by administering paraquat (PQ) twice a week for 6 weeks. After the final PQ injection, motor and cognitive functions were evaluated, followed by histological analysis. Animals treated with the mRVG9R-PRDX3 complex showed a clear reduction in PQ-induced PD symptomatology and prevented cellular senescence in the substantia nigra's neuronal population. The mRVG9R-PRDX3 gene therapy improved motor and cognitive functions in the PD animal model and demonstrated potential in protecting substantia nigra dopaminergic neurons from PQ-induced death.

Keywords: Antioxidant; Cell-penetrating peptide; Neuroprotection; PRDX3; Parkinson's disease; RVG9R.