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001     270146
005     20240630004242.0
024 7 _ |a 10.1038/s41467-024-49196-y
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024 7 _ |a pmid:38849340
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024 7 _ |a pmc:PMC11161513
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037 _ _ |a DZNE-2024-00744
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Caldi Gomes, Lucas
|0 0000-0003-4959-2169
|b 0
245 _ _ |a Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.
260 _ _ |a [London]
|c 2024
|b Nature Publishing Group UK
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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650 _ 7 |a trametinib
|0 33E86K87QN
|2 NLM Chemicals
650 _ 7 |a Pyridones
|2 NLM Chemicals
650 _ 7 |a RNA-Binding Protein FUS
|2 NLM Chemicals
650 _ 7 |a Superoxide Dismutase-1
|0 EC 1.15.1.1
|2 NLM Chemicals
650 _ 7 |a DNA-Binding Proteins
|2 NLM Chemicals
650 _ 7 |a MicroRNAs
|2 NLM Chemicals
650 _ 7 |a C9orf72 Protein
|2 NLM Chemicals
650 _ 7 |a TARDBP protein, human
|2 NLM Chemicals
650 _ 7 |a SOD1 protein, human
|2 NLM Chemicals
650 _ 7 |a FUS protein, human
|2 NLM Chemicals
650 _ 7 |a Pyrimidinones
|2 NLM Chemicals
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: drug therapy
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a MAP Kinase Signaling System: drug effects
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Pyridones: pharmacology
|2 MeSH
650 _ 2 |a Pyridones: therapeutic use
|2 MeSH
650 _ 2 |a RNA-Binding Protein FUS: metabolism
|2 MeSH
650 _ 2 |a RNA-Binding Protein FUS: genetics
|2 MeSH
650 _ 2 |a Prefrontal Cortex: metabolism
|2 MeSH
650 _ 2 |a Transcriptome
|2 MeSH
650 _ 2 |a Superoxide Dismutase-1: genetics
|2 MeSH
650 _ 2 |a Superoxide Dismutase-1: metabolism
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: genetics
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a MicroRNAs: genetics
|2 MeSH
650 _ 2 |a MicroRNAs: metabolism
|2 MeSH
650 _ 2 |a C9orf72 Protein: genetics
|2 MeSH
650 _ 2 |a C9orf72 Protein: metabolism
|2 MeSH
650 _ 2 |a Sex Characteristics
|2 MeSH
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Sex Factors
|2 MeSH
650 _ 2 |a Pyrimidinones
|2 MeSH
700 1 _ |a Hänzelmann, Sonja
|0 0000-0003-4953-0101
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700 1 _ |a Hausmann, Fabian
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700 1 _ |a Khatri, Robin
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700 1 _ |a Oller, Sergio
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700 1 _ |a Parvaz, Mojan
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700 1 _ |a Tzeplaeff, Laura
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700 1 _ |a Pasetto, Laura
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700 1 _ |a Gebelin, Marie
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700 1 _ |a Ebbing, Melanie
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700 1 _ |a Holzapfel, Constantin
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700 1 _ |a Columbro, Stefano Fabrizio
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700 1 _ |a Scozzari, Serena
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700 1 _ |a Knöferle, Johanna
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700 1 _ |a Cordts, Isabell
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700 1 _ |a Demleitner, Antonia F
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700 1 _ |a Deschauer, Marcus
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700 1 _ |a Dufke, Claudia
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700 1 _ |a Sturm, Marc
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700 1 _ |a Zhou, Qihui
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700 1 _ |a Zelina, Pavol
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700 1 _ |a Sudria-Lopez, Emma
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700 1 _ |a Haack, Tobias B
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700 1 _ |a Streb, Sebastian
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700 1 _ |a Kuzma-Kozakiewicz, Magdalena
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700 1 _ |a Edbauer, Dieter
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700 1 _ |a Pasterkamp, R Jeroen
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700 1 _ |a Laczko, Endre
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700 1 _ |a Rehrauer, Hubert
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700 1 _ |a Schlapbach, Ralph
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700 1 _ |a Carapito, Christine
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700 1 _ |a Bonetto, Valentina
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700 1 _ |a Bonn, Stefan
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700 1 _ |a Lingor, Paul
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773 _ _ |a 10.1038/s41467-024-49196-y
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