Skip to main content

The Unfolded Protein Response in Neurodegeneration

Periodic Reporting for period 3 - UPR NEURO (The Unfolded Protein Response in Neurodegeneration)

Reporting period: 2018-09-01 to 2020-02-29

This proposal aims to increase our understanding of the role of translational failure in human neurodegenerative diseases. There is currently no cure for any neurodegenerative condition and they pose an ever-increasing medical, social and economic burden on society and health care systems worldwide. They are now the leading cause of death in developed world and the number of people with neurodegenerative disease worldwide is projected to increase as the population ages. However, the molecular pathogenesis of these disorders is still largely unknown and no disease modifying treatments exist. While they are all separate diseases, Alzheimer’s (AD), Parkinson’s (PD), tauopathies including Progressive Supranuclear Palsy (PSP) and frontotemporal dementia (FTD), and the rare prion diseases, all have in common the accumulation of misfolded disease-specific proteins in the brain with associated neuronal loss. It is likely therefore, that as well as possible disease-specific effects, they share common mechanisms of disease
We recently discovered the mechanism by which protein misfolding leads to neurodegeneration in prion disease. The pathway involved is a generic cellular pathway, a branch of the unfolded protein response (UPR) that controls protein synthesis at the level of initiation of translation. Rising levels of misfolded prion protein cause sustained over-activation of the PERK-eIF2α branch of the UPR in neurons resulting in an uncompensated decline in global translation rates, synaptic failure and neuronal death. Reduction of eIF2α-P levels by genetic manipulation or by pharmacological inhibition of PERK, rescue vital translation rates and prevent neurodegeneration and clinical disease in prion-infected mice. There is increasing evidence that UPR dysregulation is a central process in protein misfolding neurodegenerative diseases, and that maintaining translation levels is essential for neuronal health. Raised levels of PERK-P and eIF2α-P occur in brains of patients with Alzheimer’s (AD), Parkinson’s (PD), and related diseases. The pathway is also implicated in learning and memory; manipulation of eIF2α-P levels boost cognition in wild type mice and restore memory deficits in AD mouse models.
Our aim is to increase insight into the role of UPR-mediated translational failure in human neurodegenerative disease and determine its tractability for the treatment of dementia. Specifically:
1. We will test for over-activation of PERK/eIF2α-P and the effects of its manipulation in other models of neurodegenerative disease.
2. We will generate new transgenic mouse models that isolate translational failure from specific misfolded proteins and
3. We will use these models to gain valuable new insights into the window for intervention when neurons can still be rescued, the selective vulnerability of different neuronal populations, and the role of the UPR in neurons and glia.
So far during this project:
1. We have shown that over activation of the PERK/eIF2a-P branch of the UPR and reduction in translation occurs in other models of neurodegenerative disease, including a model of Frontotemporal Dementia. This overactivation coincides with accumulation of the disease-associated misfolded protein, synaptic loss and precedes neuronal loss. Crucially, as in the prion disease model, pharmacological inhibition of PERK, rescues vital translation rates and prevents neurodegeneration. (Radford H. et al., Acta Neuropathologica 2015)
2. We have also discovered, in a parallel project, that two repurposed drugs target the UPR in a safe and effective way preventing neurodegeneration in two models of disease. (Halliday M. et al., Brain 2017)( http://www.bbc.co.uk/news/health-39641123)
3. Work is ongoing to develop new models of disease based on the over activation of the UPR and understanding the selective vulnerability of different neuronal populations as well as the role of the UPR in neurons and glia. This work is currently being prepared for publication.
The discovery of two repurposed drugs has open up avenues for clinical trial in AD and PD (http://www.bbc.co.uk/news/health-39641123) and new projects to deepen mechanistic understanding around PERK/eIF2a-P modulation and new drug development. Further, it has led to clinical trials in Alzheimer’s and Parkinson patients to measure Cerebral Protein Synthesis rates using PET imagining.
This work has also contributed to the formation of an UK Dementia Research Institute centre at the University of Cambridge (https://ukdri.ac.uk/centres/cambridge) led by Prof Mallucci, and the donation of private funds to form the Cambridge Centre for Parkinson’s Plus.