The UPR and synaptic dysfunction in neurodegeneration.

Activation of the unfolded protein response (UPR) is emerging as a common theme in neurodegenerative diseases, seen in both human brain tissue and mouse models. Genetic and pharmacological manipulation of the pathway in several mouse models has shown that this is not a passive consequence of the neurodegeneration process. Rather, over-activation of the PERK branch of the UPR directly contributes to disease pathogenesis through the critical reduction in neuronal protein synthesis rates via the phosphorylation of eIF2α. eIF2α-P levels are critical to learning and memory in health also; the sustained high levels in neurodegenerative disease results both in impaired learning and memory and to loss of synapse numbers and function essential for neuronal survival. Pharmacological inhibition of this process is strikingly neuroprotective in several models, leading to the discovery of the first small molecule to prevent neurodegeneration in vivo. Critically, this represents a generic approach for boosting memory and the prevention of neurodegeneration through rescue of synapses across the spectrum of these disorders, with few exceptions, independent of disease-specific proteins. Targeting the UPR, and particularly eIF2α-P-mediated translational failure is emerging as a compelling strategy for rescuing synaptic failure and neuronal loss for new treatments for dementia and neurodegenerative disease. This article is part of a Special Issue entitled SI:ER stress.