Targeting the unfolded protein response as a potential therapeutic in prion disease

Many neurodegenerative disorders, including Alzheimer's (AD), Parkinson's (PD) and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. The UPR is a protective cellular mechanism that is induced during periods of cellular and endoplasmic reticulum stress. UPR activation aims to restore protein homeostasis, by reducing protein translation, and up-regulating chaperone proteins that assist with proper protein folding. However, sustained activation of this pathway results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. Inhibiting the UPR by genetic means has recently been shown to be neuroprotective in prion disease (Moreno et al., 2012). A drug screen was performed in the model organism C. elegans to search for inhibitors of the UPR. 34 compounds were identified, of which five were selected for further analysis in C. elegans before being tested as a potential treatment in prion diseased mice. Two compounds, dibenzoylmethane and trazodone hydrochloride displayed efficacy against prion disease, and represent novel therapeutic targets. GSK2606414, a specific inhibitor of PERK (protein kinase RNA-like endoplasmic reticulum kinase), a key mediator of the UPR induced translational repression was also tested in prion diseased mice. It restored protein synthesis and prevented the development of clinical prion disease. These data validate the UPR as a viable target in prion disease, and uncover promising potential therapeutics

PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia

The PERK-eIF2α branch of the Unfolded Protein Response (UPR) mediates the transient shutdown of translation in response to rising levels of misfolded proteins in the endoplasmic reticulum. PERK and eIF2α activation are increasingly recognised in postmortem analyses of patients with neurodegenerative disorders, including Alzheimer’s disease, the tauopathies and prion disorders. These are all characterised by the accumulation of misfolded disease-specific proteins in the brain in association with specific patterns of neuronal loss, but the role of UPR activation in their pathogenesis is unclear. In prion-diseased mice, overactivation of PERK-P/eIF2α-P signalling results in the sustained reduction in global protein synthesis, leading to synaptic failure, neuronal loss and clinical disease. Critically, restoring vital neuronal protein synthesis rates by inhibiting the PERK-eIF2α pathway, both genetically and pharmacologically, prevents prion neurodegeneration downstream of misfolded prion protein accumulation. Here we show that PERK-eIF2α-mediated translational failure is a key process leading to neuronal loss in a mouse model of frontotemporal dementia, where the misfolded protein is a form of mutant tau. rTg4510 mice, which overexpress the P301L tau mutation, show dysregulated PERK signalling and sustained repression of protein synthesis by 6 months of age, associated with onset of neurodegeneration. Treatment with the PERK inhibitor, GSK2606414, from this time point in mutant tau-expressing mice restores protein synthesis rates, protecting against further neuronal loss, reducing brain atrophy and abrogating the appearance of clinical signs. Further, we show that PERK-eIF2α activation also contributes to the pathological phosphorylation of tau in rTg4510 mice, and that levels of phospho-tau are lowered by PERK inhibitor treatment, providing a second mechanism of protection. The data support UPR-mediated translational failure as a generic pathogenic mechanism in protein-misfolding disorders, including tauopathies, that can be successfully targeted for prevention of neurodegeneration