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

Información del proyecto

muscleTDP

Identificador del acuerdo de subvención: 101149165

DOI

10.3030/101149165

Fecha de la firma de la CE 12 Marzo 2024

Fecha de inicio 1 Junio 2024

Fecha de finalización 31 Mayo 2026

Financiado con arreglo a

• Marie Skłodowska-Curie Actions (MSCA)

Coste total

Sin datos

Aportación de la UE

€ 203 464,32

Coordinado por

STICHTING RADBOUD UNIVERSITEIT
Netherlands

Objetivo

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.

Ámbito científico (EuroSciVoc)

• ingeniería y tecnología › ingeniería de materiales › fibras
• ciencias naturales › ciencias biológicas › genética › ARN

Palabras clave

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

Programa(s)

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

Tema(s)

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

Régimen de financiación

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

Convocatoria de propuestas

HORIZON-MSCA-2023-PF-01

Coordinador

STICHTING RADBOUD UNIVERSITEIT

• Aportación neta de la UEn: € 203 464,32
• Dirección: HOUTLAAN 4 ; 6525 XZ Nijmegen ; Países Bajos
• Región: Oost-Nederland › Gelderland › Arnhem/Nijmegen
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: Sin datos