Neurodegenerative and Neuromuscular Disorders

Aims

This WP proposes to use the “Neurodegenerative and neuromuscular disorders” as a model to identify genetic and environmental factors that can have positive or negative effects upon ageing process

Leader name(s)

Pr V. Paquis-Flucklinger
Pr F. Checler

General description

Multiple molecular, cellular, structural and functional changes occur during ageing. Cells may respond to these changes adaptively or they may succumb to degenerative cascades that result in human pathologies such as Alzheimer’s (AD) and Parkinson’s diseases, motor neuron disorders or myopathies. Neural and muscle cells are the prime targets of this WP to study the main events involved in normal and pathological ageing.

The team is composed on the one hand by clinicians who lead several ” Reference Centres” dedicated to AD, amyotrophic lateral sclerosis (ALS), mitochondrial diseases, neuromuscular disorders… and on the other hand by scientists, experts in studying corresponding molecular mechanisms. Cohorts of patients with biological samples are available to validate pathogenic mechanisms, to improve diagnosis and follow-up, to perform clinical trials and to test solutions for fighting loss of autonomy

Task Title
Cognitive decline in neurodegenerative disorders: a model for brain ageing
Task Description

The goal is here to

  1. identify common denominators between AD and other neurodegenerative pathologies like Parkinson’s and prion diseases
  2. study the influence of oxidative stress and fatty acids on cognitive decline of AD patients and, (iii) 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.
Task Improvement
  • Develop clinically relevant biomarkers and new therapies
  • Propose new assessment tools for diagnosis and follow up of patients with cognitive disorders.
  • Improve knowledge of the cognitive and behavioural disturbances associated with loss of autonomy in ageing
  • Reachable in 3 years
Task Title
Role of telomeres in AD and brain ageing
Task Description

In order to elucidate the role of telomere metabolism in AD and brain ageing, the goal here is

  1. to study the telomere integrity in aged and AD brain samples of 3xTg-AD mice and human biopsies,
  2. to analyse the role of TRF2 in the sensitivity toward Aβ aggregates and,
  3. to determine the involvement of TRF2 in AD pathogenesis using the 3xTg AD mouse model.
Task Improvement
  • Improve knowledge of the role of telomeres in AD pathogenesis
  • Improve knowledge of the value of telomere analyses in predicting AD onset and outcome
  • Develop new cellular and mouse models for AD studies and drug screening
  • Identify and characterization of new therapeutical targets to treat AD patients
  • Reachable in 5 years
Task Title
Mitochondrial dysfunction as a primary trigger of motor neuron degeneration
Task Description

The recent identification of CHCHD10 provided genetic proof that mitochondrial dysfunction can have a causative effect in ALS, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and other motor neuron disorders. The goal here is

  1. to compare the effects of CHCHD10 mutations leading to different clinical phenotypes,
  2. to understand how the mitochondrial inner membrane organizing system (MICOS) complex disassembly leads to motor neuron degeneration by using mouse models and iPSCs that carry CHCHD10 mutations and
  3. to develop therapeutic strategies in ALS secondary to mitochondrial dysfunction
Task Improvement
  • Understand the role of mitochondrial dysfunction in motor neuron cell death
  • Understand how CHCHD10 mutations can lead either to severe (ALS) or mild (SMAJ) motor neuron diseases
  • Understand the link between mtDNA instability and ALS
  • Develop novel cellular (iPSs) and mouse models of ALS and test therapeutic strategies to fight mitochondrial dysfunction
  • Reachable in 3 years
Task Title
Muscle disorders and mechanisms linking muscle dystrophies and rhabdomyosarcomas
Task Description

The goal is here

  1. to study the impact of ageing in the evolution of neuromuscular diseases at genetic, epigenetic, metabolic and immunological level and,
  2. to perform a comparative approach between rhabdomyosarcomas and muscle dystrophies
  3. to identify altered effectors of apoptosis that could constitute therapeutic targets in these pathologies.
Task Improvement
  • Improve knowledge of the molecular pathogenesis of corresponding diseases
  • Design new animal models to analyse effects of ageing in neuromuscular disorders and to test whether cell death/survival balance restoration can reverse disease phenotypes
  • Shed light on the role of apoptosis in muscle wasting found in dystrophies
  • Reachable in 4 years