Regulation of HSP90AA1/NRF2 by BDNF Contributes to the Attenuation of Rotenone-Induced Oxidative Stress in Parkinson's Disease Models.
Xie Song, Cao Wanwan, Guo Jun, Zhao Mengfan, Wang Linxi, Liang Feiteng, Wang Zhao
Abstract
Parkinson's disease, a neurodegenerative disorder, is characterized by the degeneration of dopaminergic neurons and the accumulation of α-synuclein, both of which are aggravated by oxidative stress. This study utilized rotenone-treated SH-SY5Y cells to assess cell viability, ROS levels, and mitochondrial function. RNA-seq, mass spectrometry, and Co-IP analyses identified BDNF-regulated proteins linked to oxidative stress. In rotenone-induced PD mice, evaluations were made of motor performance, neuronal degeneration, and protein expression. Results showed that a 36-h exposure to 0.5 µM rotenone significantly increased ROS production, impaired mitochondrial function, and caused cellular damage in SH-SY5Y cells, effects which were reversed by BDNF overexpression. In mice, BDNF overexpression in the substantia nigra pars compacta alleviated PD-like symptoms. Co-IP analysis showed that BDNF modulates NRF2 and its associated proteins via HSP90AA1. These findings demonstrate that BDNF alleviates rotenone-induced oxidative stress in PD models through the HSP90AA1/NRF2 pathway, offering critical insights into the pathogenesis and potential therapeutic strategies for Parkinson's disease.
Key Findings
- Rotenone exposure significantly increased ROS production, impaired mitochondrial function, and caused cellular damage in SH-SY5Y cells.
- BDNF overexpression reversed rotenone-induced oxidative stress and cellular damage in vitro.
- In PD mouse models, BDNF overexpression in the substantia nigra pars compacta alleviated motor deficits and neuronal degeneration.
- BDNF modulates NRF2 and its associated proteins via HSP90AA1, contributing to the attenuation of oxidative stress.
Clinical Significance
These findings suggest that targeting the BDNF-HSP90AA1-NRF2 pathway may offer a novel therapeutic strategy to reduce oxidative stress and neurodegeneration in Parkinson's disease.
Citation
Xie Song, Cao Wanwan, Guo Junet al.. Regulation of HSP90AA1/NRF2 by BDNF Contributes to the Attenuation of Rotenone-Induced Oxidative Stress in Parkinson's Disease Models. Molecular neurobiology. 2026-May-02.