Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory

Abstract

Recent evidence has placed the unfolded protein response (UPR) at the centre of pathological processes leading to neurodegenerative disease. The translational repression caused by UPR activation starves neurons of the essential proteins they need to function and survive. Restoration of protein synthesis, via genetic or pharmacological means, is neuroprotective in animal models, prolonging survival. This is of great interest due to the observation of UPR activation in the post mortem brains of patients with Alzheimer's, Parkinson's, tauopathies and prion diseases. Protein synthesis is also an essential step in the formation of new memories. Restoring translation in disease or increasing protein synthesis from basal levels has been shown to improve memory in numerous models. As neurodegenerative diseases often present with memory impairments, targeting the UPR to both provide neuroprotection and enhance memory provides an extremely exciting novel therapeutic target.

Keywords: memory; neurodegeneration; neurodegenerative diseases; therapeutics; unfolded protein response.

Figure 1

UPR and ISR signalling through eIF2α‐P. Unfolded proteins induce the induction of the UPR, which signals through PERK, IRE1 and ATF6. PERK phosphorylates eIF2α, leading to the rapid attenuation of protein synthesis. Chronic reduction in protein synthesis can lead to memory impairment and neurodegeneration. eIF2α‐P also leads to the selective translation of some proteins such as ATF4 and the pro‐apoptotic CHOP. Other kinases activated by cellular stress, such as PKR and GCN2, can also phosphorylate eIF2α. GADD34 dephosphorylates eIF2α‐P, restoring translation to normal levels. The PERK inhibitor GSK2606414 and the compound ISRIB prevent neurodegeneration and improve memory, respectively. Salubrinal inhibits eIF2α‐P dephosphorylation, exacerbating neurodegeneration in some, but not all models. ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; eIF2α‐P, phosphorylated eIF2α; GNC2, general control non‐derepressible‐2; IRE1, inositol‐requiring enzyme 1; ISR, integrated stress response; PERK, PKR‐like endoplasmic reticulum kinase; PKR, protein kinase RNA; UPR, unfolded protein response; XBP1, x‐box binding protein 1.

Figure 2

Manipulation of the UPR rescues protein translation and is neuroprotective in prion‐diseased mice. Lentivirally delivered shRNA against PrP (blue bar) or overexpression of GADD34 (yellow bar) reduces levels of eIF2α‐P, restoring global protein synthesis rates, as measured by ³⁵S‐methionine incorporation levels, compared with uninfected mice (white), untreated prion‐diseased mice (black) or empty vector controls (grey). Salubrinal (brown) had a detrimental effect in the same experiments. The restoration of translation provided neuroprotection (panels). Bar chart shows mean ± standard error of the mean (**P < 0.01). Adapted from Moreno et al. [47]. LV, lentivirus; PrP, protease‐resistant prion protein; shRNA, short hairpin RNA; UPR, unfolded protein response; wpi, weeks post‐infection.

Figure 3

PERK inhibition by GSK2606414 prevents clinical disease in prion‐infected mice. Mice were treated with GSK2606414 (blue) or vehicle (red) from 7 wpi. GSK2606414 restored global protein synthesis rates and prevented loss of novel object memory, providing marked neuroprotection in the hippocampus. Pictures show clinical cure in treated mice with normal posture and movement of hind legs. Bar chart shows mean ± standard error of the mean. Controls represent uninfected mice (white bar) (n = 12 for each) (*P < 0.01). Adapted from [51]. PERK, PKR‐like endoplasmic reticulum kinase; wpi, weeks post‐infection.

Figure 4

The role of the UPR in long‐term memory formation. A learning stimulus leads to short‐term memory formation. The process of consolidation, which requires transcription and translation, cements short‐term memories into long‐term memories. The UPR can inhibit this process via eIF2α‐P‐mediated translational repression and inhibition of the transcription factor CREB by ATF4. ATF4, activating transcription factor 4; CREB, cAMP response element‐binding protein; eIF2α‐P, phosphorylated eIF2α; ISR, integrated stress response; UPR, unfolded protein response.