Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampaldependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head traumainduced chronic cognitive deficits.brain trauma | memory deficits | translational control | eIF2α | hippocampus T raumatic brain injury (TBI) represents a major mental health problem (1-4). Even a mild TBI can elicit cognitive deficits, including permanent memory dysfunction (2, 4). Moreover, TBI is one of the most predictive environmental risk factors for the development of Alzheimer's disease and other forms of dementia (5-9). Current treatments have focused primarily on reducing the risk of TBI incidence, immediate neurosurgical intervention, or broad behavioral rehabilitation (10-13). Despite posing a huge societal problem, there are currently no pharmacological treatment options for patients that suffer from TBIinduced cognitive deficits.The integrated stress response (ISR) is an evolutionarily conserved pathway that controls cellular homeostasis and function (14). The central ISR regulatory step is the phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α) by a family of four eIF2α kinases (15, 16). Phosphorylation of eIF2α leads to inhibition of general protein synthesis, but also, to the translational up-regulation of a select subset of mRNAs (17, 18). In the brain, phosphorylation of eIF2α regulates the formation of long-term memory (19)(20)(21). Briefly, animals with reduced phosphorylation of eIF2α show enhanced long-term memory storage (19,(22)(23)(24), and increased phosphorylation of eIF2α in the brain prevents the formation of long-term memory (19,24,25).Similar to other chronic cognitive disorders (21, 26), TBI leads to a persistent activation of the ISR. TBI induces eIF2α phosphorylation even in brain regions that are distal to the injury site (27, 28). How...

Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

“…Altered eIF2 phosphorylation and ISR activation contribute to a wider range of pathological conditions than those described above. These include a range of disorders where memory is altered or are neurodegenerative, such as schizophrenia (Trinh et al, 2012), Alzheimer's (Ma et al, 2013), prion disease (Moreno et al, 2012), amyotrophic lateral sclerosis (Kim et al, 2014), and head or other nerve trauma (Chou et al, 2017;Larhammar et al, 2017). Typically defects in the normal regulation of eIF2 phosphorylation or the expression of ISR-responsive mRNAs such as ATF4 have been described.…”

Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule

“…As a well-characterized small molecule with rapid cross-blood-brain barrier equilibration, reasonable bioavailability, and good tolerability in rodent efficacy models, ISRIB and related analogs offer great potential for treating VWMD and a range of other devastating diseases lacking therapeutic options (18, 26). Indeed in rodents, ISRIB entirely reverses cognitive deficits associated with traumatic brain injuries (27) and protects against neurodegeneration (26). …”

XPRESSyourself: Enhancing, Standardizing, and Automating Ribosome Profiling Computational Analyses Yields Improved Insight into Data

“…focused on in the study. However, re-analysis of these data with the updated XPRESSpipe methodology identifies genes with apparent translational down-regulation that may play a role in the neurodegenerative effects of ISR and the neuroprotective properties of ISRIB [73][74][75][76]. Importantly, several of these genes were not identified as having significantly down-regulated TEs in the original analysis, which suggests a rationale for not focusing on translational downregulation.…”

“…A recently discovered small-molecule inhibitor of the ISR, ISRIB, has been demonstrated to be a potentially safe and effective neuroprotective therapeutic for traumatic brain injury and other neurological diseases. Interestingly, ISRIB can suppress the damaging chronic low activation of the ISR, while it does not interfere with a cytoprotective acute, high-grade ISR, adding to its wide pharmacological interest [9,[71][72][73][74][75][76].…”