Activation of PERK Elicits Memory Impairment through Inactivation of CREB and Downregulation of PSD95 After Traumatic Brain Injury

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Tanusree SenNilkantha Sen

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 GSK2656...Continue Reading

Citations

Jan 23, 2019·CNS Neuroscience & Therapeutics·Yun-Jian DaiZhong Chen
Aug 8, 2018·Cold Spring Harbor Perspectives in Biology·Wayne S Sossin, Mauro Costa-Mattioli
Nov 28, 2018·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Nilkantha Sen
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