PTENα is responsible for protection of brain against oxidative stress during aging.

Neural cells are continuously subjected to oxidative stress arising from electrochemical activity, and cellular protection systems can turn on the oxidative stress response to detect and alleviate adverse conditions. However, the function and mechanism of the protective systems are complicated and remain largely elusive. We report that PTENα, an isoform of the PTEN family, mediates defense signaling in response to oxidative stress during brain aging. We show that genetic ablation of Ptenα in mice increases oxidative stress and results in neuronal cell death, culminating in accelerated decline of cognition and motor coordination as age increases. PTENα maintains COX activity and promotes energy metabolism through abrogating NEDD4L-mediated degradation of COX4 in response to oxidative stress. In the presence of Parkinson's disease-associated mutation, PTENα loses the capability to protect COX4 and ameliorate defects caused by Ptenα deletion. Our study reveals an important role of PTENα in response to oxidative stress. We propose that dysregulation of PTENα signaling may accelerate the rate of brain aging and promote the development of neurodegenerative disorders.