Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target

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 () and Paul Lingor ()
Additional contact information
Lucas Caldi Gomes: Clinical Department of Neurology
Sonja Hänzelmann: University Medical Center Hamburg-Eppendorf
Fabian Hausmann: University Medical Center Hamburg-Eppendorf
Robin Khatri: University Medical Center Hamburg-Eppendorf
Sergio Oller: University Medical Center Hamburg-Eppendorf
Mojan Parvaz: Clinical Department of Neurology
Laura Tzeplaeff: Clinical Department of Neurology
Laura Pasetto: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Marie Gebelin: Université de Strasbourg, Infrastructure Nationale de Protéomique
Melanie Ebbing: University Medical Center Hamburg-Eppendorf
Constantin Holzapfel: University Medical Center Hamburg-Eppendorf
Stefano Fabrizio Columbro: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Serena Scozzari: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Johanna Knöferle: Clinical Department of Neurology
Isabell Cordts: Clinical Department of Neurology
Antonia F. Demleitner: Clinical Department of Neurology
Marcus Deschauer: Clinical Department of Neurology
Claudia Dufke: University of Tübingen
Marc Sturm: University of Tübingen
Qihui Zhou: German Center for Neurodegenerative Diseases (DZNE)
Pavol Zelina: University Medical Center Utrecht, Utrecht University
Emma Sudria-Lopez: University Medical Center Utrecht, Utrecht University
Tobias B. Haack: University of Tübingen
Sebastian Streb: ETH Zürich and University of Zürich
Magdalena Kuzma-Kozakiewicz: Medical University of Warsaw
Dieter Edbauer: German Center for Neurodegenerative Diseases (DZNE)
R. Jeroen Pasterkamp: University Medical Center Utrecht, Utrecht University
Endre Laczko: ETH Zürich and University of Zürich
Hubert Rehrauer: ETH Zürich and University of Zürich
Ralph Schlapbach: ETH Zürich and University of Zürich
Christine Carapito: Université de Strasbourg, Infrastructure Nationale de Protéomique
Valentina Bonetto: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Stefan Bonn: University Medical Center Hamburg-Eppendorf
Paul Lingor: Clinical Department of Neurology

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49196-y

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