The potential contribution of skeletal muscle to TDP-43 associated ALS.

Informations projet

muscleTDP

N° de convention de subvention: 101149165

DOI

10.3030/101149165

Date de signature de la CE 12 Mars 2024

Date de début 1 Juin 2024

Date de fin 31 Mai 2026

Financé au titre de

• Marie Skłodowska-Curie Actions (MSCA)

Coût total

Aucune donnée

Contribution de l’UE

€ 203 464,32

Coordonné par

STICHTING RADBOUD UNIVERSITEIT
Netherlands

Objectif

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron degeneration that leads to progressive muscle atrophy. Currently only a few FDA-approved drugs are available for ALS, which merely extend patients life by a few months. Thus, there is an urgent need for new and more effective disease-modifying treatments. Although ALS is characterized by selective motor neuron degeneration, extensive evidence indicates that other cell types contribute to both onset and progression of ALS. An unresolved question in the ALS field is whether skeletal muscle fibers are merely bystanders or rather active contributors to motor neuron degeneration in ALS, and if so, through which biological pathways. Previous and ongoing work by the host laboratory has demonstrated the contribution of skeletal muscle in FUS-ALS, (1-2% of ALS cases). As TDP-43 cytoplasmic inclusions are a universal feature in nearly all ALS patients, assessing whether mutant TDP-43 toxicity in muscle contributes to ALS may be relevant to the broad community of ALS patients. I hypothesize that TDP-43 toxicity in skeletal muscle contributes to motor neuron degeneration and ALS-related phenotypes through specific molecular programs. I will use genetic and viral approaches to modulate mutant TDP-43 levels specifically in skeletal muscle in a TDP-43-ALS mouse model, and assess the effects on ALS-related phenotypes. Moreover, I will use single-nucleus RNA sequencing, a cutting-edge technique that became recently available, to determine for the first time the biological function of TDP-43 in skeletal muscle in the context of ALS, and to potentially identify novel therapeutic targets. Indeed, if mutant TDP-43 expression in skeletal muscle would influence the age of disease onset and/or disease progression, this would imply that therapeutic strategies for ALS should not only target motor neurons but also skeletal muscles, potentially improving ALS treatment approaches.

Champ scientifique (EuroSciVoc)

• ingénierie et technologie › ingénierie des materiaux › fibres
• sciences naturelles › sciences biologiques › génétique › ARN

Mots‑clés

• Amyotrophic Lateral Sclerosis
• TDP-43
• Skeletal muscle
• neurodegenetation
• single-nuclei RNAseq
• mouse genetics
• transcriptomics
• molecular neuroscience

Programme(s)

• HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) PROGRAMME PRINCIPAL
  

Thème(s)

• HORIZON-MSCA-2023-PF-01-01 - MSCA Postdoctoral Fellowships 2023
  

Régime de financement

HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

Appel à propositions

HORIZON-MSCA-2023-PF-01

Coordinateur

STICHTING RADBOUD UNIVERSITEIT

• Contribution nette de l'UE: € 203 464,32
• Adresse: HOUTLAAN 4 ; 6525 XZ Nijmegen ; Pays-Bas
• Région: Oost-Nederland › Gelderland › Arnhem/Nijmegen
• Type d’activité: Higher or Secondary Education Establishments
• Coût total: Aucune donnée