TFEB-dependent autophagy-lysosomal pathway is required for NRF2-driven antioxidative action in obstructive sleep...

Nearly one billion individuals worldwide suffer from obstructive sleep apnea (OSA) and are potentially impacted by related neurodegeneration. TFEB is considered a master regulator of autophagy and lysosomal biogenesis, but little is known about its role in neuronal oxidative stress and resultant injury induced by OSA. This study aimed to investigate these issues. Here, we demonstrated that neuronal TFEB induction is repressed in OSA mouse models. Activation of a TFEB-dependent autophagy-lysosomal pathway (ALP) reduces hippocampal neuronal cell death and mitigates OSA-related cognitive impairment. Neuronal NRF2 induction was also found to be defective in OSA mouse models. A series of staining assays for HO1, SOD3, ROS, GSH, 8-OHdG, MDA and PI revealed that enhancement of NRF2 expression restores neuronal redox balance and protects hippocampal neurons. We then identified a novel interplay between TFEB-dependent ALP and NRF2-mediated relief of oxidative stress. Inhibition of NRF2 hinders TFEB expression and lysosomal biogenesis. Conversely, knockdown of TFEB or blocking autophagy dampens the antioxidative effect of NRF2. Our findings highlight the unexpected and crucial role of TFEB-dependent ALP as a downstream event of NRF2 in NRF2-promoted redox balance. This study provides novel insights into the mechanism behind NRF2-driven antioxidative action and the regulation of TFEB-dependent ALP.