Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice

Abstract

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. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.

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.…”

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

“…Thus, targeting the intra-axonal ISR or UPR might present a novel therapeutic approach to prevent or slow down disease progression in AD by inhibiting the local synthesis of ATF4. For example, recently small molecule inhibitors of PERK or eIF2α have been described that could potentially be used to uncouple axonal stress responses from retrograde neurodegenerative signals [84,85], thereby preventing the spread of AD pathology. By specifically targeting the UPR or eIF2α, these small molecule would not change the intra-axonal synthesis of potentially restorative proteins but instead act fairly selectively to suppress the translation of Atf4 and thereby prevent the retrograde spread of pathology without interfering with local, potentially prosurvival translation events.…”

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

“…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). Importantly, this molecule can penetrate the blood-brain barrier, showing therapeutic potential for brain disease.…”