# 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

## TL;DR

The study shows that RIG-I-mediated immune activation in motor neurons causes neurodegeneration in FUS-ALS and suggests JAK inhibitors as a potential personalized treatment.

## Contribution

The study identifies RIG-I-mediated innate immune signaling as a novel therapeutic target in FUS-ALS.

## Key findings

- Increased mitochondrial transcription leads to elevated cytosolic dsRNA in FUS-ALS motor neurons.
- RIG-I knockdown and JAK-STAT inhibition reduce neurodegeneration in FUS-ALS models.
- Eight out of 18 FUS-ALS patients showed elevated interferon signatures in peripheral blood.

## 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.

Using iPSC‐derived motoneurons and postmortem tissue from FUS‐ALS patients, it is demonstrated that increased mitochondrial transcription leads to elevated cytosolic double‐stranded RNA (dsRNA) levels. This aberrant accumulation activates a RIG‐I–dependent innate immune response leading to neurodegeneration, which is amenable for FDA‐ and EMA‐approved JAK inhibitors providing an interesting novel individualized biomarker‐driven therapeutic approach for (FUS‐) ALS.