DataVXAdvanced SciencePaper
journal article·2026-03Open access

RIG‐I Mediated Neuron‐Specific IFN Type 1 Signaling in FUS‐ALS Induces Neurodegeneration and Offers New Biomarker‐Driven Individualized Treatment Options for (FUS‐)ALS

Marcel Naumann, Theresa M. Wierschin, Stefanie Kretschmer, Banaja P. Dash, Aaron Held, Andrea Salzinger, Kevin Peikert, Anže Karlek, Hannes Glaß, Dajana Großmann, René Günther, Susanne Petri, Annekathrin Rödiger, David Brenner, Francisco Pan‐Montojo, Eleonora Aronica, Markus Kipp, Vitaly Zimyanin, Jared Sterneckert, Torsten Grehl, Noah D. Seebacher, Tobias M. Böckers, Alberto Catanese, Brian J. Wainger, Patrick Oeckl, Min Ae Lee‐Kirsch, Andreas Hermann

Advanced Science· Volume 13· Issue 18
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Abstract

ABSTRACT Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS‐STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS‐ALS. Therefore, we analyzed innate immune pathways in FUS‐ALS, which revealed upregulation of interferon‐stimulated genes (ISGs) and activation of the TBK1‐IRF3 pathway in FUS mut iPSC‐derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG‐I, but not MDA5, was found to be significantly upregulated in FUS mut sMNs, which was abolished upon siRNA‐mediated knockdown of RIG‐I. RIG‐I was highly expressed in FUS‐ALS post‐mortem α‐MNs. IFN treatment of FUS wt sMNs phenocopied the axonal degeneration of FUS mut sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS‐ALS sMNs. The JAK‐STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS‐ALS patients, eight of whom had a significantly elevated interferon signature. RIG‐I‐mediated innate immune activation in sMNs may be an interesting novel individualized biomarker‐driven therapeutic target in (FUS‐) ALS. A one‐sentence summary of your paper : RIG‐I‐mediated innate immune activation is found in FUS‐ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK‐STAT inhibition and might thus be an interesting novel individualized biomarker‐driven therapeutic approach in (FUS‐) ALS.
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Research context

OpenAlex topics: Amyotrophic Lateral Sclerosis Research · interferon and immune responses · Neuroinflammation and Neurodegeneration Mechanisms

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Translational Neurodegeneration Section “Albrecht Kossel” Department of Neurology University Medical Center Rostock University of Rostock Rostock Germany

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Neurology Sean M. Healey & AMG Center for ALS Harvard Medical School Massachusetts General Hospital Boston Massachusetts USA

Center For Transdisciplinary Neurosciences Rostock (CTNR) University Medical Center Rostock University of Rostock Rostock Germany

Department of Neurology University Hospital Carl Gustav Carus At Technische Universität Dresden Dresden Germany

German Center for Neurodegenerative DIseases (DZNE) Dresden Dresden Germany

Department of Neurology Hannover Medical School Hannover Germany

Department of Neurology Jena University Hospital Jena Germany

Department of Neurology University Hospital Ulm Ulm Germany

Dept. of Psychiatry and Psychotherapy at the Klinikum LMU, Munich Germany and Neurologische Klinik Sorpesee Sundern Germany

Neurosciences Area Biogipuzkoa Health Research Institute Donostia/San Sebastian Spain

CIBERNED ISCIII (CIBER, Carlos III Institute, Spanish Ministry of Sciences and Innovation) Madrid Spain

Amsterdam UMC University of Amsterdam Department of (Neuro)Pathology Amsterdam Neuroscience Amsterdam The Netherlands

Rostock University Medical Center Institute of Anatomy Rostock Germany

Department of Molecular Physiology and Biological Physics School of Medicine University of Virginia Charlottesville Virginia USA

Center For Membrane and Cell Physiology School of Medicine University of Virginia Charlottesville Virginia USA

Center For Regenerative Therapies TU Dresden (CRTD) and the Medizinische Fakultät Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Neurology Alfried Krupp Hospital Essen Germany

Institute of Anatomy and Cell Biology University of Ulm Ulm Germany

German Center for Neurodegenerative Diseases (DZNE) Ulm Ulm Germany

Institute of Neuroanatomy University Clinic Aachen Aachen Germany

Department of Anesthesiology Critical Care and Pain Medicine Massachusetts General Hospital Boston Massachusetts USA

Broad Institute of Harvard University and MIT Cambridge Massachusetts USA

University Centre for Rare Diseases University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

German Center for Child and Adolescent Health (DZKJ), partner site Leipzig/Dresden Dresden Germany

Funding

Stichting ALS Nederland · Hermann und Lilly Schilling-Stiftung für Medizinische Forschung

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