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Multiomic Profile Integration Reveals Early Signatures of Amyotrophic Lateral Sclerosis and Suggests the MAPK Pathway as a Therapeutic Target

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and still lacks effective disease-modifying treatments. Here, we performed a multiomic analysis of the prefrontal cortex from 51 sporadic ALS patients and 50 control subjects, as well as from four transgenic mouse models of C9orf72-, SOD1-, TDP-43-, and FUS-ALS to characterize early disease mechanisms in ALS. An integrated analysis of transcriptomes, (phospho-)proteomes, and miRNAomes revealed marked sex-specific differences, more pronounced in males. We identified four transcriptome-based sALS-subclusters that are driven by pathways involved in mitochondrial respiration, synaptic function, immune response and transcription. Diffusion pseudo time estimation suggested that these clusters may represent temporal states in disease progression. Individual omics and multifactorial factor analysis revealed the mitogen-activated protein kinase (MAPK) pathway as a disease-relevant mechanism. Its modulation by trametinib in vitro and in vivo validated MEK2 as an auspicious therapeutic target for a subgroup of ALS patients.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Marie GEBELIN

LAB HEAD: Christine Carapito

PROVIDER: PXD043300 | Pride | 2024-05-16

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	C9_mzTab.mzTab.gz	Mztab
	FUS_mzTab.mzTab.gz	Mztab
	HumanMQ_pSP_GM_20200824.fasta	Fasta
	Human_mzTab.mzTab.gz	Mztab
	Human_parameters.txt	Txt

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Multiomic Profile Integration Reveals Early Signatures of Amyotrophic Lateral Sclerosis and Suggests the MAPK Pathway as a Therapeutic Target

Project description:Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and still lacks effective disease-modifying treatments. Here, we performed a multiomic analysis of the prefrontal cortex from 51 sporadic ALS patients and 50 control subjects, as well as from four transgenic mouse models of C9orf72-, SOD1-, TDP-43-, and FUS-ALS to characterize early disease mechanisms in ALS. An integrated analysis of transcriptomes, (phospho-)proteomes, and miRNAomes revealed marked sex-specific differences, more pronounced in males. We identified four transcriptome-based sALS-subclusters that are driven by pathways involved in mitochondrial respiration, synaptic function, immune response and transcription. Diffusion pseudo time estimation suggested that these clusters may represent temporal states in disease progression. Individual omics and multifactorial factor analysis revealed the mitogen-activated protein kinase (MAPK) pathway as a disease-relevant mechanism. Its modulation by trametinib in vitro and in vivo validated MEK2 as an auspicious therapeutic target for a subgroup of ALS patients.

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