Affiliations 

  • 1 School of Science, Monash University Malaysia, Jalan Lagoon Selatan, 47500, Selangor, Malaysia
  • 2 School of Biological Engineering, College of Advanced Interdisciplinary Science and Technology, Henan University of Technology, 100 Lianhua Street, Zhongyuan District, Zhengzhou, 450001, China
  • 3 School of Science, Monash University Malaysia, Jalan Lagoon Selatan, 47500, Selangor, Malaysia. ng.chenseng@monash.edu
Commun Biol, 2025 Mar 02;8(1):347.
PMID: 40025162 DOI: 10.1038/s42003-025-07790-w

Abstract

Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS), particularly in cases with SOD1 mutations. Using integrative transcriptomics, we analyzed gene expression changes in mouse models throughout progression, human induced-pluripotent stem cells (hiPSCs), and post-mortem spinal cord tissue from ALS patients. We identified a conserved upregulation of interferon (IFN) genes and IFN-stimulating genes (ISGs) in both mouse models and human ALS, with a predominance Type I IFNs (IFN-α/β) in mice and Type II IFNs (IFN-γ) in humans. In mouse models, we observed robust and sustained upregulation of Type I and II ISGs, including ATF3, beginning at disease onset stage and persisting throughout disease progression. Single-cell transcriptomics further pinpointed vascular endothelial cells as a major source of ISGs. Furthermore, we found that the STING-TBK1 axis is essential for the induction of Type II ISGs in ALS, as its deletion impaired their expression. Our study uncovers a conserved ISGs signature across ALS models and patients, highlighting the potential role of innate immune activation in ALS pathogenesis. These findings suggest that ISGs may serve as potential biomarkers and therapeutic targets for ALS.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.