Journal Article

DZNE-2024-00744

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.

Caldi Gomes, L. ; Hänzelmann, S. ; Hausmann, F. ; Khatri, R. ; Oller, S. ; Parvaz, M. ; Tzeplaeff, L. ; Pasetto, L. ; Gebelin, M. ; Ebbing, M. ; Holzapfel, C. ; Columbro, S. F. ; Scozzari, S. ; Knöferle, J. ; Cordts, I. ; Demleitner, A. F. ; Deschauer, M. ; Dufke, C. ; Sturm, M. ; Zhou, Q.DZNE* ; Zelina, P. ; Sudria-Lopez, E. ; Haack, T. B. ; Streb, S. ; Kuzma-Kozakiewicz, M. ; Edbauer, D.DZNE* ; Pasterkamp, R. J. ; Laczko, E. ; Rehrauer, H. ; Schlapbach, R. ; Carapito, C. ; Bonetto, V. ; Bonn, S.Extern* ; Lingor, P. (Last author)DZNE*

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-49196-y

Abstract: 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.

Keyword(s): Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: drug therapy (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Humans (MeSH) ; Female (MeSH) ; Animals (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Transgenic (MeSH) ; MAP Kinase Signaling System: drug effects (MeSH) ; Disease Models, Animal (MeSH) ; Pyridones: pharmacology (MeSH) ; Pyridones: therapeutic use (MeSH) ; RNA-Binding Protein FUS: metabolism (MeSH) ; RNA-Binding Protein FUS: genetics (MeSH) ; Prefrontal Cortex: metabolism (MeSH) ; Transcriptome (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; Superoxide Dismutase-1: metabolism (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; Middle Aged (MeSH) ; MicroRNAs: genetics (MeSH) ; MicroRNAs: metabolism (MeSH) ; C9orf72 Protein: genetics (MeSH) ; C9orf72 Protein: metabolism (MeSH) ; Sex Characteristics (MeSH) ; Aged (MeSH) ; Sex Factors (MeSH) ; Pyrimidinones (MeSH) ; trametinib ; Pyridones ; RNA-Binding Protein FUS ; Superoxide Dismutase-1 ; DNA-Binding Proteins ; MicroRNAs ; C9orf72 Protein ; TARDBP protein, human ; SOD1 protein, human ; FUS protein, human ; Pyrimidinones

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Adaptive Immunity in Neurodegeneration (AG Zhou)
3. Cell Biology of Neurodegeneration (AG Edbauer)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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