Human neurodevelopmental defects in accelerated ageing
Description: Aging and neurodegeneration represent profound scientific and societal challenges. Understanding the molecular mechanisms that accelerate or delay these processes is critical for developing interventions to enhance human healthspan. In this project, we propose a novel approach to uncover and target the molecular pathways driving accelerated aging and neurodegeneration by studying Cockayne syndrome (CS), a genetic disorder characterized by premature aging, neurodevelopmental defects, and neurodegeneration due to mutation of a single gene. CS offers a unique model for investigating aging-related degenerative processes, particularly as a subset of patients with the same genetic mutations exhibits a resilient phenotype—the cause of which remains unknown and will be explored in our experimental paradigm. CS uniquely combines neurodevelopmental and neurodegenerative processes, which typically occur at different stages of life. This provides a rare opportunity to explore mechanistic links between these processes. While most CS patients appear normal at birth, in a few tested cases, neurological defects manifest prenatally, raising the question of whether CS-related degeneration is purely postnatal or also driven by prenatal defects. Using advanced neural organoids, 3D structures that recapitulate early human brain development, allows us to investigate both complex neurodevelopmental dynamics over time and potentially later degenerative processes in a human-relevant system. This approach is essential as animal models poorly replicate the human disease. Supported by substantial preliminary data, which led to our novel molecular hypothesis for CS, we aim to dissect the mechanisms underlying neural defects in CS and uncover new therapeutic targets for both pathological and physiological aging-related degeneration.
Funder: Agence Nationale de la Recherche
Amount: €389,800
Funding type: research
Funder scheme: AAPG2025
Start date: 2026-01-01
Investigator: Miria RICCHETTI
Institution: INSTITUT PASTEUR
Funded outputs count: 0
Funder award ID: ANR-25-CE16-3703
OpenAlex ID: G366834636