Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target - Département Recherches Subatomiques
Article Dans Une Revue Nature Communications Année : 2024

Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target

Lucas Caldi Gomes
Sonja Hänzelmann
Fabian Hausmann
Robin Khatri
Sergio Oller
  • Fonction : Auteur
Mojan Parvaz
  • Fonction : Auteur
Laura Pasetto
  • Fonction : Auteur
Melanie Ebbing
  • Fonction : Auteur
Constantin Holzapfel
  • Fonction : Auteur
Stefano Fabrizio Columbro
  • Fonction : Auteur
Serena Scozzari
  • Fonction : Auteur
Johanna Knöferle
  • Fonction : Auteur
Antonia F Demleitner
Claudia Dufke
Qihui Zhou
  • Fonction : Auteur
Emma Sudria-Lopez
  • Fonction : Auteur
Sebastian Streb
Dieter Edbauer
R. Jeroen Pasterkamp
Endre Laczko
Hubert Rehrauer
Ralph Schlapbach
  • Fonction : Auteur
Valentina Bonetto
Stefan Bonn
Paul Lingor

Résumé

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.
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Dates et versions

hal-04708681 , version 1 (25-09-2024)

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Lucas Caldi Gomes, Sonja Hänzelmann, Fabian Hausmann, Robin Khatri, Sergio Oller, et al.. Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target. Nature Communications, 2024, 15 (1), pp.4893. ⟨10.1038/s41467-024-49196-y⟩. ⟨hal-04708681⟩
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