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

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

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
07 Jun 2024

Historique:

received: 03 08 2023

accepted: 28 05 2024

medline: 8 6 2024

pubmed: 8 6 2024

entrez: 7 6 2024

Statut: epublish

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.

Identifiants

DOI: 10.1038/s41467-024-49196-y PMID: 38849340

pubmed: 38849340

doi: 10.1038/s41467-024-49196-y

pii: 10.1038/s41467-024-49196-y

doi:

Substances chimiques

trametinib 33E86K87QN

Pyridones 0

RNA-Binding Protein FUS 0

Superoxide Dismutase-1 EC 1.15.1.1

DNA-Binding Proteins 0

MicroRNAs 0

C9orf72 Protein 0

TARDBP protein, human 0

SOD1 protein, human 0

FUS protein, human 0

Pyrimidinones 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

4893

Subventions

Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)

ID : 01GM1917A

Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)

ID : SFB1192 PB8, and PC3

Informations de copyright

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