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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE234246 | GEO | 2024/04/22

REPOSITORIES: GEO

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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.

2024-05-16 | PXD043297 | Pride

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

2024-05-16 | PXD051889 | Pride

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

2024-05-16 | PXD043300 | Pride

Multiomic Profile Integration Reveals Early Signatures of Amyotrophic Lateral Sclerosis and Suggests the MAPK Pathway as a Therapeutic Target [RNA-Seq]

Project description:The study conducted a multiomic analysis of the prefrontal cortex from 51 sporadic ALS patients and 50 control subjects, as well as four transgenic mouse models ( C9orf72, SOD1, TDP-43 and FUS) of ALS with each 5 males/females and 5 case/control samples. The analysis identified sex-specific differences in early disease mechanisms.

2024-04-22 | GSE234245 | GEO

Multiomic Profile Integration Reveals Early Signatures of Amyotrophic Lateral Sclerosis and Suggests the MAPK Pathway as a Therapeutic Target [miRNA-Seq]

2024-04-22 | GSE234243 | GEO

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

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

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Multiomic Profile Integration Reveals Early Signatures of Amyotrophic Lateral Sclerosis and Suggests the MAPK Pathway as a Therapeutic Target [miRNA-Seq]

Project description:Multiomic Profile Integration Reveals Early Signatures of Amyotrophic Lateral Sclerosis and Suggests the MAPK Pathway as a Therapeutic Target [miRNA-Seq]

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Multiomic Profile Integration Reveals Early Signatures of Amyotrophic Lateral Sclerosis and Suggests the MAPK Pathway as a Therapeutic Target [RNA-Seq]

Project description:Multiomic Profile Integration Reveals Early Signatures of Amyotrophic Lateral Sclerosis and Suggests the MAPK Pathway as a Therapeutic Target [RNA-Seq]

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Oxidative Stress as a Therapeutic Target in Amyotrophic Lateral Sclerosis: Opportunities and Limitations.

Project description:Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) and Lou Gehrig's disease, is characterized by a loss of the lower motor neurons in the spinal cord and the upper motor neurons in the cerebral cortex. Due to the complex and multifactorial nature of the various risk factors and mechanisms that are related to motor neuronal degeneration, the pathological mechanisms of ALS are not fully understood. Oxidative stress is one of the known causes of ALS pathogenesis. This has been observed in patients as well as in cellular and animal models, and is known to induce mitochondrial dysfunction and the loss of motor neurons. Numerous therapeutic agents have been developed to inhibit oxidative stress and neuroinflammation. In this review, we describe the role of oxidative stress in ALS pathogenesis, and discuss several anti-inflammatory and anti-oxidative agents as potential therapeutics for ALS. Although oxidative stress and antioxidant fields are meaningful approaches to delay disease progression and prolong the survival in ALS, it is necessary to investigate various animal models or humans with different subtypes of sporadic and familial ALS.

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<i>UNC13A</i> in amyotrophic lateral sclerosis: from genetic association to therapeutic target.

Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the UNC13A gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.

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