Aims
This WP proposes to understand the mechanisms leading to cancer or neurodegenerative and neuromuscular disorders in specific disease models, with a focus on ageing related changes as a tiebreaker, and common denominators that could underlie molecular interplays between these pathologies.
Leader name(s)
Pr S. Sacconi
Pr. C. Fallandry
Dr F. Checler
General description
Researchers have noted an inverse correlation between the odds of getting cancer and of developing neurodegenerative diseases. While ageing and neurodegeneration are marked by suppression of cell cycle genes and induction of inflammatory genes, the opposite happens in cancer. More recently, several genes involved in hereditary neurodegenerative or neuromuscular diseases have been found somatically deregulated in several types of cancer. The mechanisms tuning the shift toward cancer and hereditary or acquired neurodegenerative or neuromuscular diseases is still poorly known. Ageing related changes -including genetic and epigenetic modifications, telomere shortening, immune system deregulation; cell death- may represent a tradeoff between these two different pathways. We would like to investigate in specific models of neurodegenerative and neuromuscular disorders and in cancer convergent and divergent pathways leading to dysregulated cellular proliferation or cell death and degeneration. Understanding these pathways should pave the way to the development of new therapeutic strategies for these diseases.
- Task Title
- Molecular and cognitive dysfunctions in neurodegenerative disorders: a model for brain ageing
- Task Description
The goals are: 1. To identify common denominators between AD and other neurodegenerative pathologies like Parkinson’s and prion diseases and between degenerative disorders and brain cancers 2. To study the influence of oxidative stress and fatty acids on cognitive decline of AD patients and, (iii) to develop and validate Information and Communication Technology (ICT) tools for diagnosis, follow-up, treatment and environment (including social and psychological aspects) of patients with cognitive disorders. 3. To develop clinically relevant biomarkers and new therapies 4. To propose new assessment tools for diagnosis and follow up of patients with cognitive disorders.
- Task Improvement
5.To improve knowledge of the cognitive and behavioural disturbances associated with loss of autonomy in ageing Reachable in 3 years
- Task Title
- “DUX4 related neuromuscular diseases and cancer: finding the link and developing new therapeutic strategies ”
- Task Description
The goals are: 1. To study the frequency of cancer in FSHD patients and to collect biological samples (blood, urine, cells, tissues) 2. To study the frequency of DUX4 related cancer and to collect biological samples (blood, urine, cells, tissues) 3. To study the impact of ageing (genetic and epigenetic changes, telomere shortening, deregulation of the immune system, metabolic changes) in these models and to perform a comparative approach between DUX4 induced cancer and facioscapulohumeral muscular dystrophy 4. To identify altered effectors of apoptosis in both disease models that could be involved in tipping the balance and may constitute therapeutic targets in these pathologies.
- Task Improvement
To improve the knowledge of the pathogenesis of corresponding diseases and shed light on the role of ageing in muscle degeneration found in muscular dystrophies and in cancer development associated to DUX4 expression. Reachable in 4 years
- Task Title
- Role of telomeres in brain and muscle physiological and pathological ageing
- Task Description
In order to elucidate the role of telomere metabolism in brain and muscle ageing and in specific disease models (AD, IBM), the goal here is to study the telomere integrity in aged brain and muscle samples of 3xTg-AD mice and in human samples, to analyse the role of TRF2 in the sensitivity toward Aβ aggregates and to determine the involvement of TRF2 in AD pathogenesis using the 3xTg AD mouse model.
- Task Improvement
To improve knowledge of the role of telomeres in AD and IBM pathogenesis To improve knowledge of the value of telomere analyses in predicting AD and IBM onset and outcome To develop new cellular and mouse models for AD and IBM studies and drug screening To identify and characterization of new therapeutical targets to treat AD and IBM patients Reachable in 5 years