1. Academic Validation
  2. RACK1 promotes autophagy via the PERK signaling pathway to protect against traumatic brain injury in rats

RACK1 promotes autophagy via the PERK signaling pathway to protect against traumatic brain injury in rats

  • CNS Neurosci Ther. 2024 Mar;30(3):e14691. doi: 10.1111/cns.14691.
Haibo Ni 1 2 Xugang Kan 3 Qin Rui 4 Yang Zhang 3 Weiwei Zhai 1 Baole Zhang 3 Zhengquan Yu 1
Affiliations

Affiliations

  • 1 Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 2 Department of Neurosurgery, The Fourth Affiliated Hospital of Soochow University, Suzhou, China.
  • 3 Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, China.
  • 4 Department of Center of Clinical Laboratory, The Fourth Affiliated Hospital of Soochow University, Suzhou, China.
Abstract

Aims: Neuronal cell death is a primary factor that determines the outcome after traumatic brain injury (TBI). We previously revealed the importance of receptor for activated C kinase (RACK1), a multifunctional scaffold protein, in maintaining neuronal survival after TBI, but the specific mechanism remains unclear. The aim of this study was to explore the mechanism underlying RACK1-mediated neuroprotection in TBI.

Methods: TBI model was established using controlled cortical impact injury in Sprague-Dawley rats. Genetic intervention and pharmacological inhibition of RACK1 and PERK-autophagy signaling were administrated by intracerebroventricular injection. Western blotting, coimmunoprecipitation, transmission electron microscopy, Real-Time PCR, immunofluorescence, TUNEL staining, Nissl staining, neurobehavioral tests, and contusion volume assessment were performed.

Results: Endogenous RACK1 was upregulated and correlated with Autophagy induction after TBI. RACK1 knockdown markedly inhibited TBI-induced Autophagy, whereas RACK1 overexpression exerted the opposite effects. Moreover, RACK1 overexpression ameliorated neuronal Apoptosis, neurological deficits, and cortical tissue loss after TBI, and these effects were abrogated by the Autophagy Inhibitor 3-methyladenine or siRNAs targeting Beclin1 and Atg5. Mechanistically, RACK1 interacted with PERK and activated PERK signaling. Pharmacological and genetic inhibition of the PERK pathway abolished RACK1-induced Autophagy after TBI.

Conclusion: Our findings indicate that RACK1 protected against TBI-induced neuronal damage partly through Autophagy induction by regulating the PERK signaling pathway.

Keywords

PERK; RACK1; autophagy; neuroprotection; traumatic brain injury.

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