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Updated: Jan 29, 2026
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ALS - Motor Neuron Disease: Mechanism and Development of New Therapies
Published on: July 29, 2007
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RIG-I Mediated Neuron-Specific IFN Type 1 Signaling in FUS-ALS Induces Neurodegeneration and Offers New
Marcel Naumann1, Theresa M Wierschin1, Stefanie Kretschmer2
1Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 28, 2026
Summary
In FUS-ALS, RIG-I innate immune activation in spinal motor neurons stems from mitochondrial issues. This pathway can be targeted by JAK-STAT inhibitors, offering a potential new therapy for FUS-ALS patients.
Area of Science:
- Neuroimmunology
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Activation of the innate immune system is implicated in Amyotrophic Lateral Sclerosis (ALS) models.
- Cytosolic DNA sensing via cGAS-STING pathway, triggered by DNA damage and mitochondrial dysfunction, is a known innate immune activator.
- FUS-ALS pathology involves chronic DNA damage and defective mitochondria, suggesting a role for innate immunity.
Purpose of the Study:
- To investigate innate immune pathway activation in FUS-ALS, specifically focusing on FUS-mutant induced pluripotent stem cell-derived spinal motor neurons (FUSmut iPSC-sMNs).
- To identify the specific pattern recognition receptor and RNA species involved in innate immune activation in FUS-ALS.
- To explore potential therapeutic strategies targeting the identified innate immune pathways.
Main Methods:
- Analysis of interferon-stimulated genes (ISGs) and the TBK1-IRF3 pathway in FUSmut iPSC-sMNs.
- Assessment of cytosolic double-stranded RNA (dsRNA) sensors RIG-I and MDA5, and RIG-I knockdown using siRNA.
- Compartmental axonal RNA sequencing to analyze mitochondrial transcription and its impact on dsRNA accumulation.
- Treatment of FUSwild-type (FUSwt) iPSC-sMNs with interferon (IFN) and FUSmut iPSC-sMNs with JAK-STAT inhibitor ruxolitinib.
- Analysis of ISG expression in peripheral blood from FUS-ALS patients.
Main Results:
- Upregulation of ISGs and activation of the TBK1-IRF3 pathway were observed in FUSmut iPSC-sMNs.
- Accumulation of cytosolic dsRNA and its sensor RIG-I (but not MDA5) were significantly upregulated in FUSmut iPSC-sMNs, with RIG-I expression confirmed in post-mortem FUS-ALS alpha-motor neurons (α-MNs).
- IFN treatment of FUSwt iPSC-sMNs mimicked the axonal degeneration seen in FUSmut iPSC-sMNs.
- Mitochondrial transcription was upregulated and its inhibition reduced ISGs in FUS-ALS sMNs.
- Ruxolitinib treatment alleviated ISG upregulation and reversed axonal degeneration in FUS-ALS sMNs.
- Elevated interferon signatures were found in a subset of FUS-ALS patients' peripheral blood.
Conclusions:
- RIG-I-mediated innate immune activation, driven by cytosolic dsRNA from mitochondrial transcriptional dysregulation, occurs in FUS-ALS spinal motor neurons.
- This RIG-I activation contributes to axonal degeneration and is responsive to JAK-STAT inhibition.
- RIG-I activation serves as a potential biomarker and therapeutic target for individualized treatment approaches in FUS-ALS.
Keywords:
RIG‐IRIG‐I like receptorsRNA‐sequencingcGAS‐STING pathwaydouble‐stranded RNApathogen‐associated molecular patternstype 1 interferonMore Related Videos
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