Project description
DNA repair and neurodegeneration
Neurons exhibit heightened sensitivity to DNA damage, and thus DNA repair is central to maintaining genome stability. The protein encoded by the RFC1 gene is implicated in DNA replication and repair. Abnormal expansions of repetitive DNA sequences within RFC1 have emerged as a cause of adult-onset ataxia and neuropathy. The ERC-funded GEMREX project will conduct a genome-wide association study in individuals carrying RFC1 expansion to identify genetic modifiers of disease onset and progression. They will also carry out a gene perturbation study in stem cell-derived neurons to confirm the biological relevance of these modifiers. Through these experiments, combined with the analysis of patient tissues and large population databases, the researcher will aim to delineate disease pathways and identify targets for future therapeutic intervention.
Objective
Biallelic repeat expansion in RFC1, an essential gene involved in DNA replication and repair, are a leading cause of ataxia and neuropathy in the adult population.
Nonetheless, the exact mechanism linking RFC1 repeat expansion and neurodegeneration remains elusive. The prevailing hypothesis is that the repeat may lead to a partial loss of function of RFC1, by affecting expression of neuron specific RFC1 isoforms or by impairing its fine regulation in terminally differentiated neurons, including sensory neurons and Purkinje cells.
The objective of proposal is to leverage state-of the-art genomic medicine methods, including the observation of the naturally occurring genetic variation and controlled genome perturbation, to unravel disease relevant pathways.
We will perform a genome-wide association (GWA) analysis complemented by long read sequencing to identify genetic modifiers of onset, phenotype and progression of RFC1 disease. We will take advantage of the Crispri technology in genetically engineered iSensoryNeurons to further investigate the effect of GWA loci and to identify additional factors which can modulate RFC1 expression and ameliorate or exacerbate the molecular phenotype. As modifiers are likely to act at cell specific and dynamic level, genetic data will be paralleled by single-cell approaches in post mortem cerebellum and dorsal root ganglia, as well as IPSC sensory neurons and cerebellar organoids. Finally, given a high carrier frequency of RFC1 expansion nearing one out of ten people, we will try to understand whether the repeat itself can act as a modifier of common health and disease traits at population level.
The results will hopefully lead to a better understanding of disease causing mechanisms and identify potentially druggable targets. The study output may also have broader implications considering the central role of DNA repair in neuronal functioning and ageing.
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
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics genomes
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-STG
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WC1E 6BT London
United Kingdom
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