Objective
This proposal aims to increase our understanding of the role of translational failure in human neurodegenerative diseases. 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. We will test for over-activation of PERK/eIF2α-P and the effects of its manipulation in other models of neurodegenerative disease. We will generate new transgenic mouse models that isolate translational failure from specific misfolded proteins and use these 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. Collectively, the 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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- medical and health sciences medical biotechnology genetic engineering
- natural sciences biological sciences biochemistry biomolecules proteins protein folding
- medical and health sciences basic medicine neurology parkinson
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2014-CoG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
CB2 1TN CAMBRIDGE
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.