Deficiency of unc-51 like kinase 1 (U1k1) protects against mice traumatic brain injury (TBI) by suppression of p38 and JNK pathway

Unc-51 like autophagy activating kinase 1 (U1k1) is a serine/threonine kinase that plays a key role in regulating autophagy processes. We attempted to investigate the effects of U1k1 on traumatic brain injury (TBI) progression by using wild type (WT) mice and U1k1-knockout (KO) mice suffered with or not TBI. The results were verified using LPS-treated primary astrocyte (AST). Here, U1k1 was over-expressed in hippocampus of WT mice after TBI, as well as in lipopolysaccharide (LPS)-stimulated AST. U1k1 deletion improved cognitive ability and hippocampus histological changes in TBI mice. Nissl and neuronal nuclei (NeuN) staining indicated that U1k1-deletion increased the number of surviving neurons in hippocampus of TBI mice. U1k1-ablation alleviated neuroinflammation, as evidenced by the reduced expression of hippocampus pro-inflammatory cytokines in TBI mice. TBI-induced apoptosis was also ameliorated by U1k1-ablation, as proved by the reduced number of TUNEL-staining cells, and cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP) expressions. Moreover, U1k1-knockout suppressed TBI-stimulated activation of astrocytes and microglia cells. Additionally, hippocampus autophagy induced by TBI was attenuated by U1k1-knockout. Further, TBI-activated p38/c-Jun N-terminal Kinase (JNK) pathway was repressed by U1k1-deletion in hippocampus of mice. The findings above were confirmed in LPS-stimulated AST with or without U1k1 siRNA transfection. Intriguingly, pre-treatment of p38 or JNK activator markedly abolished the anti-inflammation, anti-apoptosis and anti-autophagy effects of U1k1-knockdown on LPS-incubated AST. In conclusion, our results demonstrated that U1k1 might be a potential target for developing therapeutic strategy against TBI in future. (C) 2018 Published by Elsevier Inc.