TY  - JOUR
AU  - Caldi Gomes, Lucas
AU  - Hänzelmann, Sonja
AU  - Hausmann, Fabian
AU  - Khatri, Robin
AU  - Oller, Sergio
AU  - Parvaz, Mojan
AU  - Tzeplaeff, Laura
AU  - Pasetto, Laura
AU  - Gebelin, Marie
AU  - Ebbing, Melanie
AU  - Holzapfel, Constantin
AU  - Columbro, Stefano Fabrizio
AU  - Scozzari, Serena
AU  - Knöferle, Johanna
AU  - Cordts, Isabell
AU  - Demleitner, Antonia F
AU  - Deschauer, Marcus
AU  - Dufke, Claudia
AU  - Sturm, Marc
AU  - Zhou, Qihui
AU  - Zelina, Pavol
AU  - Sudria-Lopez, Emma
AU  - Haack, Tobias B
AU  - Streb, Sebastian
AU  - Kuzma-Kozakiewicz, Magdalena
AU  - Edbauer, Dieter
AU  - Pasterkamp, R Jeroen
AU  - Laczko, Endre
AU  - Rehrauer, Hubert
AU  - Schlapbach, Ralph
AU  - Carapito, Christine
AU  - Bonetto, Valentina
AU  - Bonn, Stefan
AU  - Lingor, Paul
TI  - Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2024-00744
SP  - 4893
PY  - 2024
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: drug therapy
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Humans
KW  - Female
KW  - Animals
KW  - Male
KW  - Mice
KW  - Mice, Transgenic
KW  - MAP Kinase Signaling System: drug effects
KW  - Disease Models, Animal
KW  - Pyridones: pharmacology
KW  - Pyridones: therapeutic use
KW  - RNA-Binding Protein FUS: metabolism
KW  - RNA-Binding Protein FUS: genetics
KW  - Prefrontal Cortex: metabolism
KW  - Transcriptome
KW  - Superoxide Dismutase-1: genetics
KW  - Superoxide Dismutase-1: metabolism
KW  - DNA-Binding Proteins: metabolism
KW  - DNA-Binding Proteins: genetics
KW  - Middle Aged
KW  - MicroRNAs: genetics
KW  - MicroRNAs: metabolism
KW  - C9orf72 Protein: genetics
KW  - C9orf72 Protein: metabolism
KW  - Sex Characteristics
KW  - Aged
KW  - Sex Factors
KW  - Pyrimidinones
KW  - trametinib (NLM Chemicals)
KW  - Pyridones (NLM Chemicals)
KW  - RNA-Binding Protein FUS (NLM Chemicals)
KW  - Superoxide Dismutase-1 (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - MicroRNAs (NLM Chemicals)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - TARDBP protein, human (NLM Chemicals)
KW  - SOD1 protein, human (NLM Chemicals)
KW  - FUS protein, human (NLM Chemicals)
KW  - Pyrimidinones (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38849340
C2  - pmc:PMC11161513
DO  - DOI:10.1038/s41467-024-49196-y
UR  - https://pub.dzne.de/record/270146
ER  -