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Neurofilaments in Health and neurodegenerative diseases

Project description

Innovative live-imaging and proteomic methodologies

Neurofilaments (NFs) are a main cytoskeletal network with essential functions in neurons. NFs are mutated and implicated in neurodegeneration, where their abnormal aggregation is an early pathological hallmark of disease. The EU-funded NeuroFish project aims to decipher the physiological roles of NFs and proposes the concept that defects in NF dynamic underlies neurodegeneration. The project combines innovative live-imaging and proteomic methodologies using zebrafish. Researchers anticipate that modifications of NF dynamics will reverse neurodegeneration, and proofs of concept will be obtained by overexpressing key modulators in disease zebrafish models and through drug screening. The project will increase knowledge on NFs and has the potential to provide a platform for therapeutic interventions on NFs for the benefit of most neurodegenerative diseases.

Objective

Neurofilaments (NFs) are a highly dynamic cytoskeletal network, which exhibits essential functions in neurons and are key actors in neurodegeneration. NFs are not only a genetic cause of neuronal death in human, their abnormal aggregation is an early pathological hallmark in disease, and their genetic removal from axons has shown spectacular benefits in delaying disease onset, extending survival and restoring neurological functions in mouse models. In this project, I propose the concept that the defects in NF transport and degradation are the causes of neurodegeneration. I will tackle the live dynamic of these processes in health and disease in a meaningful in vivo context, using the zebrafish. Combining state-of-the-art and innovative live-imaging and proteomic methodologies in zebrafish, our program has three major goals. First, we will study the dynamic of NF transport along the axons and its spatial regulation by myelinating cells, with novel zebrafish lines expressing fluorescently labeled NFs. Second, we will decipher the mechanisms of NF degradation by generating a zebrafish line overexpressing gigaxonin, an E3 ligase adaptor we found to destroy the stable NF network, and by designing a new proteomic methodology in zebrafish. Finally, we will investigate NF dysfunctions and their pathological roles in disease, by generating models for neurodegenerative diseases carrying NF mutations and using the methodologies described above. I anticipate that interventions on NF dynamics will substantially reverse neurodegeneration, and proofs of concept will be obtained by overexpressing gigaxonin in our disease zebrafish models and through drug screening. Thus, this ERC project will generate forefront knowledge in the field of NFs and neurodegeneration and will provide a highly significant platform for therapeutic intervention on NFs, for the benefit of most neurodegenerative diseases.

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: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.

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Host institution

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Net EU contribution
€ 1 874 863,00
Address
RUE DE TOLBIAC 101
75654 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Links
Total cost
€ 1 874 863,00

Beneficiaries (1)

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