Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity

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.

Genesis of ER stress in Huntington’s Disease

“…Reduction of eIF2α-P [159], or treatment with a compound that restores translation downstream of eIF2α, thwarted prion-related disease in mouse models [162]. This is consistent with our results of PERK inhibition in knock-in striatal neurons expressing mutant Htt, which considerably reduced cytotoxicity [44].…”

“…In the other, cytotoxicity in cells expressing mutant prion protein (PrPSc) was increased by salubrinal, an inhibitor of GADD34, whereas overexpression of GADD34 was protective [159], suggesting that the phosphorylated state of eIF2α was responsible for the toxicity. Treatment with a compound that restores translation downstream of eIF2α prevented prion-related neurodegeneration [162].…”

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

“…Furthermore, oral treatment with a specific inhibitor of PERK both at preclinical and symptomatic stages of Prion-infected mice attenuated disease progression [163]. Similarly, treatment of animals with ISRIB, a small compound that blocks the consequences of eIF2α phosphorylation protected against PrD [164]. Of note, PERK inhibition did not attenuate PrP misfolding, suggesting that its protection was specifically linked to synaptic function improvements.…”

Mechanisms of prion-induced neurodegeneration

“…Notably, despite significantly increasing mouse survival as compared to untreated controls, ISRIB administration resulted in significant body weight loss similarly to PERK inhibition (Ref. 240). Understanding whether the observed weight loss results from UPR inhibition, it is a side effect of ISRIB treatment, or else it arises as a consequence of persistent prion infection will have important implications in the clinical implementation of this and similar drugs (Ref.…”

“…Understanding whether the observed weight loss results from UPR inhibition, it is a side effect of ISRIB treatment, or else it arises as a consequence of persistent prion infection will have important implications in the clinical implementation of this and similar drugs (Ref. 240).…”