ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2017
Activation of PERK Elicits Memory Impairment through Inactivation of CREB and Downregulation of PSD95 After Traumatic Brain Injury.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 116 citations in OpenAlex.
- Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- PERK Deficiency Amplifies Molecular, Structural, and Network Vulnerability to Repetitive Mild Traumatic Brain Injury.bioRxiv : the preprint server for biology · 2026Article
- Unveiling the role of PSD95 phosphorylation after traumatic brain injury: insights from phosphoproteomic analysis.BMC neurology · 2025Article
- Homeostasis control in health and disease by the unfolded protein response.Nature reviews. Molecular cell biology · 2025Review
- Effect of Early Inhibition of Toll-Like Receptor 4 on Hippocampal Plasticity in a Neonatal Rat Model of Hypoxic-Ischemic Brain Damage.Molecular neurobiology · 2025Article
- Claudin-1 impairs blood-brain barrier by downregulating endothelial junctional proteins in traumatic brain injury.Tissue barriers · 2025Article
- mGluR5 as a Potential Orchestrator of Astrocyte Interactions in Neurological Disorders.Neural plasticity · 2025Review
- ISR Modulators in Neurological Diseases.Current neuropharmacology · 2025Review
- Nogo-A exacerbates sepsis-associated encephalopathy by modulating microglial SHP-2/NLRP3 balance and inducing ROS and M1 polarization.Biomolecules & biomedicine · 2024Article
- Enhancing neurogenesis after traumatic brain injury: The role of adenosine kinase inhibition in promoting neuronal survival and differentiation.Experimental neurology · 2024Article
- Time-Dependent Potentiation of the PERK Branch of UPR by GPR68 Offers Protection in Brain Ischemia.Stroke · 2024Article
- The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses.Current opinion in neurobiology · 2024Review
- Mammalian integrated stress responses in stressed organelles and their functions.Acta pharmacologica Sinica · 2024Review
- ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling.iScience · 2024Article
- RACK1 promotes autophagy via the PERK signaling pathway to protect against traumatic brain injury in rats.CNS neuroscience & therapeutics · 2024Article
- Endoplasmic reticulum stress and the unfolded protein response: emerging regulators in progression of traumatic brain injury.Cell death & disease · 2024Review
- Neurotrophins and neural stem cells in posttraumatic brain injury repair.Animal models and experimental medicine · 2024Review
- Cognitive impairment in Chinese traumatic brain injury patients: from challenge to future perspectives.Frontiers in neuroscience · 2024Review
- Astrocytic deletion of protein kinase R-like ER kinase (PERK) does not affect learning and memory in aged mice but worsens outcome from experimental stroke.Journal of neuroscience research · 2023Article
- Activation of the integrated stress response by inhibitors of its kinases.Nature communications · 2023Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The PKR-like ER kinase (PERK), a transmembrane protein, resides in the endoplasmic reticulum (ER). Its activation serves as a key sensor of ER stress, which has been implicated in traumatic brain injury (TBI). The loss of memory is one of the most common symptoms after TBI, but the precise role of PERK activation in memory impairment after TBI has not been well elucidated. Here, we have shown that blocking the activation of PERK using GSK2656157 prevents the loss of dendritic spines and rescues memory deficits after TBI. To elucidate the molecular mechanism, we found that activated PERK phosphorylates CAMP response element binding protein (CREB) and PSD95 directly at the S129 and T19 residues, respectively. Phosphorylation of CREB protein prevents its interaction with a coactivator, CREB-binding protein, and subsequently reduces the BDNF level after TBI. Conversely, phosphorylation of PSD95 leads to its downregulation in pericontusional cortex after TBI in male mice. Treatment with either GSK2656157 or overexpression of a kinase-dead mutant of PERK (PERK-K618A) rescues BDNF and PSD95 levels in the pericontusional cortex by reducing phosphorylation of CREB and PSD95 proteins after TBI. Similarly, administration of either GSK2656157 or overexpression of PERK-K618A in primary neurons rescues the loss of dendritic outgrowth and number of synapses after treatment with a PERK activator, tunicamycin. Therefore, our study suggests that inhibition of PERK phosphorylation could be a potential therapeutic target to restore memory deficits after TBI.
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