Abstract
Activation of the PERK branch of the unfolded protein response (UPR) in response to protein misfolding within the endoplasmic reticulum (ER) results in the transient repression of protein synthesis, mediated by the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α). This is part of a wider integrated physiological response to maintain proteostasis in the face of ER stress, the dysregulation of which is increasingly associated with a wide range of diseases, particularly neurodegenerative disorders. In prion-diseased mice, persistently high levels of eIF2α cause sustained translational repression leading to catastrophic reduction of critical proteins, resulting in synaptic failure and neuronal loss. We previously showed that restoration of global protein synthesis using the PERK inhibitor GSK2606414 was profoundly neuroprotective, preventing clinical disease in prion-infected mice. However, this occured at the cost of toxicity to secretory tissue, where UPR activation is essential to healthy functioning. Here we show that pharmacological modulation of eIF2α-P-mediated translational inhibition can be achieved to produce neuroprotection without pancreatic toxicity. We found that treatment with the small molecule ISRIB, which restores translation downstream of eIF2α, conferred neuroprotection in prion-diseased mice without adverse effects on the pancreas. Critically, ISRIB treatment resulted in only partial restoration of global translation rates, as compared with the complete restoration of protein synthesis seen with GSK2606414. ISRIB likely provides sufficient rates of protein synthesis for neuronal survival, while allowing some residual protective UPR function in secretory tissue. Thus, fine-tuning the extent of UPR inhibition and subsequent translational de-repression uncouples neuroprotective effects from pancreatic toxicity. The data support the pursuit of this approach to develop new treatments for a range of neurodegenerative disorders that are currently incurable.
Highlights
Under physiological conditions, unfolded protein response (UPR) activation ensures proteostasis is maintained through a combination of translational and transcriptional responses triggered by the accumulation of misfolded proteins in the endoplasmic reticulum (ER).[6]
This leads to the inhibition of protein synthesis and increased expression of the transcription factor activating transcription factor 4 (ATF4) and associated downstream signaling events, in response to other cellular stresses mediated by various eukaryotic initiation factor 2 alpha (eIF2α) kinases, including PERK6 (Figure 1)
The data show that treatment with integrated stress response inhibitor (ISRIB), as with the pancreatic ER kinase (PERK) kinase inhibitor GSK2606414, is profoundly neuroprotective in prion-diseased mice (Figures 3 and 4)
Summary
UPR activation ensures proteostasis is maintained through a combination of translational and transcriptional responses triggered by the accumulation of misfolded proteins in the ER.[6]. Despite excellent neuroprotection in the brain, treatment with GSK2606414 in prion-diseased mice was associated with toxicity leading to weight loss and mild hyperglycemia,[10] a predicted consequence of PERK inhibition in the pancreas.[20] The pancreas has an extensive secretory protein synthesis load, and requires some degree of eIF2α-P-mediated translational repression to survive ER stress. These findings beg the question of whether restoration of protein synthesis to the level required to prevent neurodegeneration is obligatorily linked to dose-limiting toxicity, which is central to the further pursuit of this approach to therapy. We measured protein synthesis rates to compare the effects of the two compounds on UPR/ISRmediated translational attenuation to determine whether this can be safely manipulated for the prevention of neurodegeneration without problematic toxicity
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