WDR23 mediates NRF2 proteostasis and cytoprotective capacity in the hippocampus

Abstract

Pathogenic brain aging and neurodegenerative diseases such as Alzheimers disease and Parkinsons disease are characterized by chronic neuroinflammation and the accumulation of dysfunctional or misfolded proteins that lead to progressive neuronal cell death. Here we demonstrate that a murine model with global loss of the CUL4-DDB1 substrate receptor WDR23 (Wdr23KO) results in changes in multiple age-related hippocampal-dependent behaviors. The behavioral differences observed in Wdr23KO animals accompany the stabilization of the NRF2/NFE2L2 protein, an increase in RNA transcripts regulated by this cytoprotective transcription factor, and an increase in the steady state level of antioxidant defense proteins. Taken together, these findings reveal a role for WDR23-proteostasis in mediating cytoprotective capacity in the hippocampus and reveal the potential for targeting WDR23-NRF2 signaling interactions for development of therapies for neurodegenerative disorders. HIGHLIGHTSO_LIWDR23 regulates NRF2/NFE2L2 stability in the mouse hippocampus C_LIO_LILoss of Wdr23 significantly increases the expression of NFE2L2/NRF2 target genes C_LIO_LIGlobal loss of WDR23 influences age-related behaviors differentially in males and females C_LI