000270146 001__ 270146
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000270146 037__ $$aDZNE-2024-00744
000270146 041__ $$aEnglish
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000270146 1001_ $$00000-0003-4959-2169$$aCaldi Gomes, Lucas$$b0
000270146 245__ $$aMultiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.
000270146 260__ $$a[London]$$bNature Publishing Group UK$$c2024
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000270146 520__ $$aAmyotrophic 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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000270146 650_7 $$033E86K87QN$$2NLM Chemicals$$atrametinib
000270146 650_7 $$2NLM Chemicals$$aPyridones
000270146 650_7 $$2NLM Chemicals$$aRNA-Binding Protein FUS
000270146 650_7 $$0EC 1.15.1.1$$2NLM Chemicals$$aSuperoxide Dismutase-1
000270146 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000270146 650_7 $$2NLM Chemicals$$aMicroRNAs
000270146 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000270146 650_7 $$2NLM Chemicals$$aTARDBP protein, human
000270146 650_7 $$2NLM Chemicals$$aSOD1 protein, human
000270146 650_7 $$2NLM Chemicals$$aFUS protein, human
000270146 650_7 $$2NLM Chemicals$$aPyrimidinones
000270146 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000270146 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: drug therapy
000270146 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000270146 650_2 $$2MeSH$$aHumans
000270146 650_2 $$2MeSH$$aFemale
000270146 650_2 $$2MeSH$$aAnimals
000270146 650_2 $$2MeSH$$aMale
000270146 650_2 $$2MeSH$$aMice
000270146 650_2 $$2MeSH$$aMice, Transgenic
000270146 650_2 $$2MeSH$$aMAP Kinase Signaling System: drug effects
000270146 650_2 $$2MeSH$$aDisease Models, Animal
000270146 650_2 $$2MeSH$$aPyridones: pharmacology
000270146 650_2 $$2MeSH$$aPyridones: therapeutic use
000270146 650_2 $$2MeSH$$aRNA-Binding Protein FUS: metabolism
000270146 650_2 $$2MeSH$$aRNA-Binding Protein FUS: genetics
000270146 650_2 $$2MeSH$$aPrefrontal Cortex: metabolism
000270146 650_2 $$2MeSH$$aTranscriptome
000270146 650_2 $$2MeSH$$aSuperoxide Dismutase-1: genetics
000270146 650_2 $$2MeSH$$aSuperoxide Dismutase-1: metabolism
000270146 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000270146 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000270146 650_2 $$2MeSH$$aMiddle Aged
000270146 650_2 $$2MeSH$$aMicroRNAs: genetics
000270146 650_2 $$2MeSH$$aMicroRNAs: metabolism
000270146 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000270146 650_2 $$2MeSH$$aC9orf72 Protein: metabolism
000270146 650_2 $$2MeSH$$aSex Characteristics
000270146 650_2 $$2MeSH$$aAged
000270146 650_2 $$2MeSH$$aSex Factors
000270146 650_2 $$2MeSH$$aPyrimidinones
000270146 7001_ $$00000-0003-4953-0101$$aHänzelmann, Sonja$$b1
000270146 7001_ $$00000-0001-6110-5824$$aHausmann, Fabian$$b2
000270146 7001_ $$00009-0006-5311-1718$$aKhatri, Robin$$b3
000270146 7001_ $$aOller, Sergio$$b4
000270146 7001_ $$aParvaz, Mojan$$b5
000270146 7001_ $$00009-0003-7643-3232$$aTzeplaeff, Laura$$b6
000270146 7001_ $$aPasetto, Laura$$b7
000270146 7001_ $$aGebelin, Marie$$b8
000270146 7001_ $$aEbbing, Melanie$$b9
000270146 7001_ $$aHolzapfel, Constantin$$b10
000270146 7001_ $$aColumbro, Stefano Fabrizio$$b11
000270146 7001_ $$aScozzari, Serena$$b12
000270146 7001_ $$aKnöferle, Johanna$$b13
000270146 7001_ $$aCordts, Isabell$$b14
000270146 7001_ $$00000-0001-9557-9243$$aDemleitner, Antonia F$$b15
000270146 7001_ $$aDeschauer, Marcus$$b16
000270146 7001_ $$00000-0001-5225-2443$$aDufke, Claudia$$b17
000270146 7001_ $$00000-0002-6552-8362$$aSturm, Marc$$b18
000270146 7001_ $$0P:(DE-2719)2811347$$aZhou, Qihui$$b19$$udzne
000270146 7001_ $$aZelina, Pavol$$b20
000270146 7001_ $$aSudria-Lopez, Emma$$b21
000270146 7001_ $$00000-0001-6033-4836$$aHaack, Tobias B$$b22
000270146 7001_ $$00000-0002-9095-6596$$aStreb, Sebastian$$b23
000270146 7001_ $$aKuzma-Kozakiewicz, Magdalena$$b24
000270146 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b25
000270146 7001_ $$00000-0003-1631-6440$$aPasterkamp, R Jeroen$$b26
000270146 7001_ $$00000-0003-0271-3971$$aLaczko, Endre$$b27
000270146 7001_ $$00000-0001-7612-9394$$aRehrauer, Hubert$$b28
000270146 7001_ $$aSchlapbach, Ralph$$b29
000270146 7001_ $$00000-0002-0079-319X$$aCarapito, Christine$$b30
000270146 7001_ $$00000-0003-0456-2054$$aBonetto, Valentina$$b31
000270146 7001_ $$0P:(DE-2719)2810547$$aBonn, Stefan$$b32$$udzne
000270146 7001_ $$0P:(DE-2719)2812561$$aLingor, Paul$$b33$$eLast author
000270146 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-024-49196-y$$gVol. 15, no. 1, p. 4893$$n1$$p4893$$tNature Communications$$v15$$x2041-1723$$y2024
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