Project description
Decoding amyloid fibril formation
Protein misfolding leads to the formation of abnormal aggregates such as amyloid fibrils, which accumulate in tissues, disrupt normal cellular function and lead to various diseases such as Alzheimer's disease and Parkinson's disease. Funded by the European Research Council, the GLAM-Map project will follow a genomics approach to shed light on the aggregation rate of various proteins. Researchers will map the impact of mutations on amyloid nucleation and identify genomic sequences associated with amyloid formation. While obtaining fundamental insights into the process of amyloid fibril formation and disease prediction, the study also aims to guide the development of targeted therapeutics for amyloid diseases.
Objective
Amyloid fibrils form and precipitate in more than 50 incurable human diseases, including Alzheimer’s and Parkinson’s disease. All proteins may be able to form amyloids, at least under certain circumstances. However, aggregation is actually rare as the process of amyloid formation is controlled by a high kinetic barrier: protein sequences have to cross a free energy barrier to nucleate transition states which then seed irreversible fibril formation. Short-lived transition states are extremely challenging to study using biophysical methods. We have recently developed a massively parallel genomics approach to quantify the rate of aggregation of thousands of protein sequences. We also have evidence that, by quantifying the interactions between mutations, we can capture the key interactions between residues in the transition state. Here, we will unleash the potential of this approach by targeting the following aims:
1) Map the impact on amyloid nucleation of all possible mutations in >60 human and functional amyloids - generating reference atlases for clinical variant interpretation
2) Build an energetic and structural model of the transition state of disease-associated amyloids
3) Uncover sequences across the genome that nucleate amyloids in response to environmental stress
This project will uncover the rules required to understand, predict and engineer amyloid formation. By identifying the mutations that do and do not lead to amyloid formation, we will reveal which variants accelerate aggregation and cause disease. We will also address one of the most important questions in the field, i.e. identifying the interactions established in the transition states of amyloid nucleation, guiding the development of therapeutic approaches in amyloid diseases, including the worst kinds of dementia. Finally, our results will feed a new generation of models and predictors of protein aggregation to employ for disease variant interpretation and the synthetic design of novel proteins.
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.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesgeneticsgenomes
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
08028 Barcelona
Spain