Project description
How DNA instability drives ALS and dementia
A tiny genetic glitch can have devastating effects on the brain. In Europe, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a repeat expansion in the C9orf72 gene. It is a mutation whose destructive mechanism remains a mystery. The ERC-funded epiC9repair project aims to explore a groundbreaking explanation: that faulty DNA repair and chromatin instability at this gene’s locus trigger the chain of events leading to neuron death. Using cutting-edge CRISPR screens, chromatin mapping, and studies of patient-derived cells, the project will uncover how DNA damage and epigenetic changes drive these diseases. By pinpointing the repair pathways involved, the project aims to pave the way for therapies.
Objective
Repeat expansions are a major cause of neurodegenerative diseases, but causal therapies are not available. A (G4C2)n repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Europe. Despite extensive research, the mechanisms linking these expansions to selective neurodegeneration remain poorly understood. Our project, epiC9repair, explores the novel hypothesis that genomic instability at the C9orf72 locus, driven by aberrant DNA repair and repeat-induced chromatin changes, is a critical factor in ALS/FTD pathogenesis. This project builds on our recent observation that the C9orf72 repeat is also a hotspot of DNA synthesis in post-mitotic neurons, and on recent findings in Huntington’s disease that cell type-specific somatic expansion of the pathogenic (CAG)n repeat drives neurodegeneration by unknown mechanisms.
Using advanced CRISPR screens and innovative chromatin mapping techniques, we aim to uncover the DNA repair pathways that drive genomic instability in C9orf72 ALS/FTD and how these pathways contribute to neurodegeneration. In addition, we will investigate the role of epigenetic modifications in cell culture models and patient tissues, with a focus on identifying biomarkers that correlate with disease progression and regional neurodegeneration. These findings will inform studies in mouse models to test the therapeutic potential of targeting genomic instability. This multidisciplinary approach has the potential to transform our understanding of C9orf72-related diseases and paves the way for targeted therapeutic strategies that address the root causes of genomic instability in neurodegeneration.
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.
You need to log in or register to use this function
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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.
-
HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
See all projects funded under this programme
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.
HORIZON-ERC - HORIZON ERC Grants
See all projects funded under this funding scheme
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-2024-ADG
See all projects funded under this callHost institution
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.
53127 Bonn
Germany
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.