Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.
Fiche publication
Date publication
juin 2024
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CARAPITO Christine
Tous les auteurs :
Caldi Gomes L, Hänzelmann S, Hausmann F, Khatri R, Oller S, Parvaz M, Tzeplaeff L, Pasetto L, Gebelin M, Ebbing M, Holzapfel C, Columbro SF, Scozzari S, Knöferle J, Cordts I, Demleitner AF, Deschauer M, Dufke C, Sturm M, Zhou Q, Zelina P, Sudria-Lopez E, Haack TB, Streb S, Kuzma-Kozakiewicz M, Edbauer D, Pasterkamp RJ, Laczko E, Rehrauer H, Schlapbach R, Carapito C, Bonetto V, Bonn S, Lingor P
Lien Pubmed
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.
Mots clés
Amyotrophic Lateral Sclerosis, genetics, Humans, Female, Animals, Male, Mice, Mice, Transgenic, MAP Kinase Signaling System, drug effects, Disease Models, Animal, Pyridones, pharmacology, RNA-Binding Protein FUS, metabolism, Prefrontal Cortex, metabolism, Transcriptome, Superoxide Dismutase-1, genetics, DNA-Binding Proteins, metabolism, Middle Aged, MicroRNAs, genetics, C9orf72 Protein, genetics, Sex Characteristics, Aged, Sex Factors, Pyrimidinones
Référence
Nat Commun. 2024 06 7;15(1):4893