Chd8 Rescued TBI-Induced Neurological Deficits by Suppressing Apoptosis and Autophagy Via Wnt Signaling Pathway
Cellular and Molecular Neurobiology(2020)
Abstract
Traumatic brain injury (TBI) and autism spectrum disorder (ASDs) share several same biochemical mechanisms and symptoms, such as learning memory impairments and communication deficits. Chromodomain helicase DNA binding protein 8 (CHD8), a member of the CHD family of ATP-dependent chromatin remodeling factors, is one of the top risk genetic factors in ASDs and is highly associated with Wnt/β-catenin signaling. Yet, the possible effect of CHD8 on TBI remains poorly understood. In vivo, we found that Chd8 co-localized in neurons, astrocytes, and microglia, but predominantly presented in neurons in the prefrontal cortex, hippocampus, and cortex. Both Chd8 and β-catenin expression peaked at 12 h and shared the similar change tendency after TBI. Chd8 knockdown inhibited wnt pathway, promoted the activation of apoptosis and autophagy, and caused learning and memory impairments both at normal and TBI condition. In addition, overexpression of Chd8 via 17β-estrogen (E2) treatment enhanced wnt signaling pathway and suppressed TBI-induced apoptosis and autophagic activation. In vitro, a significant increase of Chd8 and β-catenin expression was observed in HT22 cells after lipopolysaccharide (lps) treatment or mechanical injury, respectively. Chd8 knockdown inhibited wnt signaling pathway and increased apoptosis and autophagy activation in lps-stimulated HT22 cells. But activation of wnt signaling inverted the effects of Chd8-siRNA. Our results demonstrated that Chd8 exerted neuroprotection and promoted cognitive recovery through inhibiting apoptosis and autophagy activation following TBI, at least partially by wnt signaling pathway.
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Key words
Chromodomain helicase DNA binding protein 8,Traumatic brain injury,Wnt,Apoptosis,Autophagy
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