The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway.

Daniel Hughes,Giovanna R Mallucci

doi:10.1111/febs.14422

Abstract

The unfolded protein response (UPR) is a highly conserved protein quality control mechanism, activated in response to Endoplasmic Reticulum (ER) stress. Signalling is mediated through three branches, PERK, IRE1, and ATF6, respectively, that together provide a coordinated response that contributes to overcoming disrupted proteostasis. PERK branch activation predominantly causes a rapid reduction in global rates of translation, while the IRE1 and ATF6 branch signalling induce a transcriptional response resulting in expression of chaperones and components of the protein degradation machinery. Protein misfolding neurodegenerative diseases show disruption of proteostasis as a biochemical feature. In the brains of animal models of disease and in human post mortem tissue from many of these disorders, markers of UPR induction, particularly, the PERK pathway can be observed in close association with disease progression. Recent research has revealed dysregulated UPR signalling to be a major pathogenic mechanism in neurodegeneration, and that genetic and pharmacological modulation of the PERK pathway results in potent neuroprotection. Targeting aberrant UPR signalling is the focus of new therapeutic strategies, which importantly could be beneficial across the broad spectrum of neurodegenerative diseases.

Highlights

Neurodegenerative diseases vary in their clinical, pathological and biochemical signatures
Immunoreactivity of Endoplasmic Reticulum (ER) stress markers P-protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK), P-eukaryotic Initiation Factor 2a (eIF2a) and P-inositol requiring enzyme 1 (IRE1) was observed in pretangle hippocampal neurons in several human cases of Alzheimer’s disease (AD), AD with Lewy body pathology and vascular dementia, and this immunoreactivity was most abundant in neurons with that contained ptau, the authors suggest that chronic unfolded protein response (UPR) activation is involved in both tau phosphorylation and AD pathogenesis from early disease points
Recent failures in clinical trials, those aimed at clearance of disease-specific aggregated protein such as Ab [1,2,3] supports the pursuit of additional targets

Summary

Introduction

Neurodegenerative diseases vary in their clinical, pathological and biochemical signatures. Upregulation of PERK branch UPR markers in these disorders is associated temporally and spatially with the accumulation of misfolded and aggregated protein [33,35], the authors observed high levels of P-PERK and eIF2a-P immunoreactivity in the pons of progressive supranuclear palsy (PSP) patients and in the hippocampus of Alzheimer’s sufferers in comparison to nondiseased control brains.

Results

Conclusion