Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Abstract

The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the a-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2a-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases 1-4 , but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2a-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2a-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2a-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2a-P dephosphorylation 5 , increased eIF2a-P levels, exacerbating neurotoxicity and significantly reducing survival in priondiseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.Neurodegenerative diseases pose an ever-increasing challenge for society and health care systems worldwide, but their molecular pathogenesis is still largely unknown and no curative treatments exist. Alzheimer's (AD), Parkinson's (PD) and prion diseases are separate clinical and pathological conditions, but it is likely they share common mechanisms leading to neuronal death. Mice with prion disease show misfolded prion protein (PrP) accumulation and develop extensive neurodegeneration (with profound neurological deficits), in contrast to mouse models of AD or PD, in which neuronal loss is rare. Uniquely therefore, prion-infected mice allow access to mechanisms linking protein misfolding with neuronal death. Prion replication involves the conversion of cellular PrP, PrP C , to its misfolded, aggregating conformer, PrP Sc , a process leading ultimately to neurodegeneration 6 . We have previously shown rescue of neuronal loss and reversal of early cognitive and morphological changes in prion-infected mice by depleting PrP in neurons, preventing prion replication and ab...

Multiple Mechanisms of Unfolded Protein Response–Induced Cell Death

“…85 In contrast, genetic or chemical inhibition of PERK pathway signaling using GADD34 overexpression or the PERK inhibitor glycogen synthetase kinase 2606414 ameliorates neurodegeneration in prion-infected mice, whereas activating the PERK pathway using salubrinal worsens prionassociated neurotoxicity. 83,84 These studies reveal a direct role for the PERK pathway in prion disease pathogenesis, and suggest that IRE1 signaling, at least through XBP1s generation, is dispensable in this process.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Another PERK inhibitor, GSK2606414, gave new insight into how this small molecule can be used in human disease. Prion disease, which is caused by accumulation of misfolded prion protein (PrP) due to prion replication, causes sustained activation of the PERK/eIF2α pathway (Moreno et al 2012). Oral treatment with GSK2606414 prevented UPR-mediated translational attenuation and abrogated development of prion diseases in mice (Moreno et al 2013).…”

Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

“…Neurons are especially sensitive to this inhibition because normal cerebral functions including memory formation need continuous protein synthesis. Therefore, chronic inhibition of translation is followed by neuronal death [68]. Inhibition of protein synthesis due to ribosome dysfunction is one of the earliest features of metabolic alterations in the AD brain [69].…”