Regulation of HSP90AA1/NRF2 by BDNF Contributes to the Attenuation of Rotenone-Induced Oxidative Stress in Parkinson's Disease Models

Parkinson's disease is a neurodegenerative condition characterized by dopaminergic neuron degeneration and alpha-synuclein accumulation, both exacerbated by oxidative stress. This study employed rotenone-treated SH-SY5Y cells to evaluate cell viability, ROS levels, and mitochondrial function. RNA-seq, mass spectrometry, and Co-IP identified BDNF-regulated proteins associated with oxidative stress. In rotenone-induced PD mice, assessments focused on motor performance, neuronal loss, and protein expression. Results demonstrated that exposure to 0.5 uM rotenone for 36 hours elevated ROS production, mitochondrial dysfunction, and cellular damage in SH-SY5Y cells, effects reversed by BDNF overexpression. In mice, BDNF overexpression in the substantia nigra pars compacta alleviated PD-like symptoms. Co-IP analysis revealed that BDNF modulates NRF2 and its associated proteins through HSP90AA1. Collectively, BDNF mitigates rotenone-induced oxidative stress in PD models via the HSP90AA1/NRF2 pathway, providing valuable insights into the pathogenesis and potential treatment of Parkinson's disease.