Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target
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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.
SEEK ID: http://lmmeisd-2.srv.mwn.de/studies/81
Projects: SyNergy: Published Datasets
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Created: 25th Oct 2024 at 09:30
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Projects: SyNergy: Published Datasets, SyNergy: Unpublished Datasets
Institutions: DZNE
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Projects: SyNergy: Published Datasets, SyNergy: Unpublished Datasets
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Projects: SyNergy: Published Datasets, SyNergy: Unpublished Datasets, Test Programme: Project 1
Institutions: LMU Klinikum
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Projects: SyNergy: Published Datasets, SyNergy: Unpublished Datasets
Institutions: DZNE
Please visit the 'Related items' tab within the profile page to explore associated studies in more detail.
Neurological diseases are on the rise – and as societies age, they affect an ever-increasing number of people, not only in Europe, but worldwide.
The Munich Cluster for Systems Neurology (SyNergy) investigates how complex neurological diseases such as Alzheimer's disease, stroke, and multiple sclerosis develop. Even though these diseases differ in their clinical manifestations, overlapping mechanisms are involved in their development. For example, the immune system gets activated in dementia, ...
Projects: SyNergy: Published Datasets, SyNergy: Unpublished Datasets
Web page: https://www.synergy-munich.de
This project serves as a centralized repository for omics datasets published by research groups within the SyNergy Cluster. It encompasses investigations such as proteomics and transcriptomics, which are further divided into individual studies led by SyNergy members. Each study is linked to relevant publications, assays and data files (with links to external repositories).
To explore investigations and their associated studies in more detail, please visit the 'Related items' tab on the Project ...
Programme: Munich Cluster for Systems Neurology (SyNergy)
Public web page: Not specified
Submitter: Rainer Malik
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Assays: Expression profiling: Bulk RNA-seq (human), Expression profiling: Bulk RNA-seq (human), Expression profiling: Bulk RNA-seq (human), Expression profiling: Bulk RNA-seq (human) + smallRNA-seq (human), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Bulk RNA-seq (rat), Expression profiling: MERFISH Spatial Transcriptomics (mouse), Expression profiling: Microarray (zebrafish), Expression profiling: RiboTag-mRNA-seq (mouse), Expression profiling: Small RNA-seq (human), Expression profiling: Spatial Transcriptomics (mouse), Expression profiling: Spatial Transcriptomics correlated Electron Micros..., Expression profiling: scRNA-seq (human), Expression profiling: scRNA-seq (human), Expression profiling: scRNA-seq (human), Expression profiling: scRNA-seq (human), Expression profiling: scRNA-seq (human), Expression profiling: scRNA-seq (human) (Day 20), Expression profiling: scRNA-seq (human) (Day 5), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse) + Bulk RNA-seq (mouse), Expression profiling: small RNA-seq (human), Expression profiling: small RNA-seq (mouse), Genome binding/occupancy profiling: Bulk ATAC-seq (mouse), Genome binding/occupancy profiling: Bulk ATAC-seq (mouse), Genome binding/occupancy profiling: CUT&Tag sequencing (mouse), Genome binding/occupancy profiling: snATAC-seq (mouse), Genome wide (GW) and validation CRISPR screens (rat)
Comparative small RNA expression profiling analysis for four transgenic mouse models ( C9orf72, SOD1, TDP-43 and FUS) of ALS with each 5 males/females and 5 case/control samples. For FUS one male control sample was excluded.
Submitter: Aditi Methi
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: Transcriptomics (Published)
Comparative gene expression profiling analysis of RNA-seq data for four transgenic mouse models ( C9orf72, SOD1, TDP-43 and FUS) of ALS with each 5 males/females and 5 case/control samples. For FUS one male control sample was excluded.
Submitter: Aditi Methi
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: Transcriptomics (Published)
Submitter: Aditi Methi
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: Transcriptomics (Published)
Submitter: Aditi Methi
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: Transcriptomics (Published)
Creators: None
Submitter: Aditi Methi
External LinkCreators: None
Submitter: Aditi Methi
Creators: None
Submitter: Aditi Methi
Creators: None
Submitter: Aditi Methi
Abstract (Expand)
Authors: Lucas Caldi Gomes, Sonja Hänzelmann, Fabian Hausmann, Robin Khatri, Sergio Oller, Mojan Parvaz, Laura Tzeplaeff, Laura Pasetto, Marie Gebelin, Melanie Ebbing, Constantin Holzapfel, Stefano Fabrizio Columbro, Serena Scozzari, Johanna Knöferle, Isabell Cordts, Antonia F Demleitner, Marcus Deschauer, Claudia Dufke, Marc Sturm, Qihui Zhou, Pavol Zelina, Emma Sudria-Lopez, Tobias B Haack, Sebastian Streb, Magdalena Kuzma-Kozakiewicz, Dieter Edbauer, R Jeroen Pasterkamp, Endre Laczko, Hubert Rehrauer, Ralph Schlapbach, Christine Carapito, Valentina Bonetto, Stefan Bonn, Paul Lingor
Date Published: 1st Jul 2024
Publication Type: Journal
