Summary
Mutations in certain proteins can cause their misfolding and aggregation, posing a potential threat to the health of an organism. Protein aggregation is counteracted by protein quality control (PQC) mechanisms that reduce the amounts of damaged molecules. As we age, however, the crucial surveillance mechanisms weaken and become less effective, leading to protein misfolding diseases. The most well-known protein disorders, or proteinopathies – Alzheimer's, Huntington's, and Parkinson's diseases – are characterized by the formation of toxic protein aggregates, known as amyloids. Current research focuses on such amyloid diseases, however, there seem to be many other, hidden protein disorders. In principle, every mutation in a protein can affect its folding and stability and may become pathological only when PQC mechanisms are compromised. To better understand this kind of proteinopathy, we will generate novel PQC tools and study muscle protein disorders in the nematode Caenorhabditis elegans. We will design dual-colour fluorescent protein reporters to monitor the misfolding and aggregation of disease-linked myosin variants, our model proteins. The ‘MyoState’ library, comprising hundreds of mutants with a broad range of folding defects, will allow us to study the pathological impact of individual myopathy mutations and investigate cellular rescue mechanisms. In C. elegans, myosin disease mutations cause characteristic defects in motility and muscle structure, which can be rescued by dietary restriction. This animal model thus provides us with a unique opportunity to perform genome-wide screens that will define the PQC network in muscle cells. By performing structural and functional analyses of key factors in this network, we aim to reveal the fundamental mechanisms of myosin quality control and its regulation. Our ultimate goal is to understand how the misfolding of functional proteins, whether due to mutation or age, impairs cell function.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101141607 |
| Start date: | 01-01-2025 |
| End date: | 31-12-2029 |
| Total budget - Public funding: | 2 498 824,00 Euro - 2 498 824,00 Euro |
Cordis data
Original description
Mutations in certain proteins can cause their misfolding and aggregation, posing a potential threat to the health of an organism. Protein aggregation is counteracted by protein quality control (PQC) mechanisms that reduce the amounts of damaged molecules. As we age, however, the crucial surveillance mechanisms weaken and become less effective, leading to protein misfolding diseases. The most well-known protein disorders, or proteinopathies – Alzheimer's, Huntington's, and Parkinson's diseases – are characterized by the formation of toxic protein aggregates, known as amyloids. Current research focuses on such amyloid diseases, however, there seem to be many other, hidden protein disorders. In principle, every mutation in a protein can affect its folding and stability and may become pathological only when PQC mechanisms are compromised. To better understand this kind of proteinopathy, we will generate novel PQC tools and study muscle protein disorders in the nematode Caenorhabditis elegans. We will design dual-colour fluorescent protein reporters to monitor the misfolding and aggregation of disease-linked myosin variants, our model proteins. The ‘MyoState’ library, comprising hundreds of mutants with a broad range of folding defects, will allow us to study the pathological impact of individual myopathy mutations and investigate cellular rescue mechanisms. In C. elegans, myosin disease mutations cause characteristic defects in motility and muscle structure, which can be rescued by dietary restriction. This animal model thus provides us with a unique opportunity to perform genome-wide screens that will define the PQC network in muscle cells. By performing structural and functional analyses of key factors in this network, we aim to reveal the fundamental mechanisms of myosin quality control and its regulation. Our ultimate goal is to understand how the misfolding of functional proteins, whether due to mutation or age, impairs cell function.Status
SIGNEDCall topic
ERC-2023-ADGUpdate Date
15-10-2024
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