Partial restoration of protein synthesis rates by the small molecule ISRIB prevents @entity179 without pancreatic XXXX .

@entity137 @entity5085 @entity2986 @entity19 @entity3124 @entity22643 @entity179 @entity71619 @entity528
UNASSIGNED: Activation of the @entity2986 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 ( @entity22643 ). This is part of a wider integrated physiological response to maintain @entity5085 in the face of ER stress, the dysregulation of which is increasingly associated with a wide range of diseases, @entity179 . In prion-diseased @entity19 , persistently high levels of @entity22643 cause sustained translational repression leading to catastrophic @entity3124 , resulting in synaptic failure and @entity528 . We previously showed that restoration of global protein synthesis using the @entity2986 inhibitor @entity71619 was profoundly neuroprotective, preventing clinical disease in prion-infected @entity19 . However, this occured at the cost of @entity137 to secretory tissue, where UPR activation is essential to healthy functioning. Here we show that pharmacological modulation of @entity22643 -P-mediated translational inhibition can be achieved to produce neuroprotection without pancreatic @entity137 . We found that treatment with the small molecule ISRIB, which restores translation downstream of @entity22643 , conferred neuroprotection in prion-diseased @entity19 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 @entity71619 . 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 @entity137 . The data support the pursuit of this approach to develop new treatments for a range of @entity179 that are currently incurable.
