Journal Article

DZNE-2026-00310

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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.

Naumann, M. ; Wierschin, T. M. ; Kretschmer, S. ; Dash, B. P. ; Held, A. ; Salzinger, A. ; Peikert, K. ; Karlek, A. ; Glaß, H. ; Großmann, D. ; Günther, R.DZNE* ; Petri, S. ; Rödiger, A. ; Brenner, D.Extern* ; Pan-Montojo, F. ; Aronica, E. ; Kipp, M. ; Zimyanin, V. ; Sterneckert, J. ; Grehl, T. ; Seebacher, N. D.Extern* ; Böckers, T. M.DZNE* ; Catanese, A.DZNE* ; Wainger, B. J. ; Oeckl, P.DZNE* ; Lee-Kirsch, M. A. ; Hermann, A. (Last author)DZNE*

2026
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/advs.202417135

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 FUSmut 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 FUSmut 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 FUSwt sMNs phenocopied the axonal degeneration of FUSmut 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.

Keyword(s): Humans (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: immunology (MeSH) ; Signal Transduction (MeSH) ; Motor Neurons: metabolism (MeSH) ; Biomarkers: metabolism (MeSH) ; DEAD Box Protein 58: metabolism (MeSH) ; DEAD Box Protein 58: genetics (MeSH) ; RNA-Binding Protein FUS: genetics (MeSH) ; RNA-Binding Protein FUS: metabolism (MeSH) ; Interferon Type I: metabolism (MeSH) ; Receptors, Immunologic: metabolism (MeSH) ; Immunity, Innate (MeSH) ; RIG‐I ; RIG‐I like receptors ; RNA‐sequencing ; cGAS‐STING pathway ; double‐stranded RNA ; pathogen‐associated molecular patterns ; type 1 interferon ; Biomarkers ; DEAD Box Protein 58 ; RIGI protein, human ; RNA-Binding Protein FUS ; Interferon Type I ; Receptors, Immunologic

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Contributing Institute(s):

1. Translational Neurodegeneration (AG Hermann)
2. Translational Parkinson Research (AG Falkenburger)
3. Translational Protein Biochemistry (AG Böckers)
4. Translational Mass Spectrometry and Biomarker Research (AG Öckl)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2026

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Database coverage:
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