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

• Published in: Nature communications Vol. 15; no. 1; pp. 4893 - 23
• Main Authors: Caldi Gomes, Lucas, Hänzelmann, Sonja, Hausmann, Fabian, Khatri, Robin, Oller, Sergio, Parvaz, Mojan, Tzeplaeff, Laura, Pasetto, Laura, Gebelin, Marie, Ebbing, Melanie, Holzapfel, Constantin, Columbro, Stefano Fabrizio, Scozzari, Serena, Knöferle, Johanna, Cordts, Isabell, Demleitner, Antonia F., Deschauer, Marcus, Dufke, Claudia, Sturm, Marc, Zhou, Qihui, Zelina, Pavol, Sudria-Lopez, Emma, Haack, Tobias B., Streb, Sebastian, Kuzma-Kozakiewicz, Magdalena, Edbauer, Dieter, Pasterkamp, R. Jeroen, Laczko, Endre, Rehrauer, Hubert, Schlapbach, Ralph, Carapito, Christine, Bonetto, Valentina, Bonn, Stefan, Lingor, Paul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/63; 38; 38/22; 38/23; 38/47; 38/90; 38/91; 631/337/2019; 631/378/1689/1285; 631/378/87; 64/60; 82/58; 82/80; Aged; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animal models; Animals; Biochemistry, Molecular Biology; C9orf72 Protein - genetics; C9orf72 Protein - metabolism; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Extracellular matrix; Female; Females; FUS gene; Genomics; Human health and pathology; Humanities and Social Sciences; Humans; Immune response; Inhibitor drugs; Kinases; Life Sciences; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Mice; Mice, Transgenic; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Molecular modelling; Motor neuron diseases; multidisciplinary; Neurobiology; Neurons and Cognition; Pharmaceutical sciences; Pharmacology; Prefrontal cortex; Prefrontal Cortex - metabolism; Proteomes; Pyridones - pharmacology; Pyridones - therapeutic use; Pyrimidinones; RNA processing; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism; Science; Science (multidisciplinary); Sex Characteristics; Sex differences; Sex Factors; Signatures; Subgroups; Superoxide dismutase; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Therapeutic targets; Tissue analysis; Transcriptome; Transcriptomes; Transgenic mice
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49196-y

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. Multiomic brain tissue analysis identified sex-specific molecular changes in Amyotrophic lateral sclerosis (ALS), revealing subgroups within the disease and pointing to the MAPK pathway as an early disease mechanism and potential therapeutic target.