Activation of interferon signaling pathways in spinal cord astrocytes from an ALS mouse model

• Published in: Glia Vol. 59; no. 6; pp. 946 - 958
• Main Authors: Wang, Rengang, Yang, Bo, Zhang, Dongxian
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2011
• Subjects: Age; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animal models; Animals; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Cells, Cultured; Disease Models, Animal; Endoplasmic reticulum; Female; gene expression; Glial cells; Humans; Interferon; Interferon Type I - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; motor neuron; Motor neurons; neurodegenerative disease; Neurodegenerative diseases; neuron-glia interaction; Neuronal-glial interactions; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - genetics; Signal transduction; Signal Transduction - physiology; Spinal cord; Spinal Cord - metabolism; Spinal Cord - pathology; Superoxide dismutase; Transcription; Transcription factors; Transgenic mice
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.21167

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting predominantly motor neurons. Recent studies suggest that the disease progression of ALS is non‐cell‐autonomous, although the interaction between neurons and glial cells in different disease stages is not entirely clear. Here, we demonstrate that the interferon (IFN) signaling pathway is activated in human SOD1(G93A) transgenic mice, a rodent model of ALS. IFN‐stimulated genes (ISGs) increased in the spinal cord of SOD1(G93A) mice at a presymptomatic age. In addition, the up‐regulated ISGs, and most likely their transcriptional activators, were found specifically in astrocytes surrounding motor neurons, suggesting that IFN signaling in astrocytes was triggered by specific pathologic changes in motor neurons. Furthermore, induction of ISGs in cultured astrocytes was highly sensitive to IFN, especially Type I IFN. ISGs in astrocytes were activated specifically by endoplasmic reticulum stress‐induced neurodegeneration in vitro, implicating a similar process in the presymptomatic stage of SOD1 mutant mice. Finally, reduction or deletion of IFNα receptor 1 inhibited IFN signaling and increased the life‐span of SOD1(G93A) mice. Thus, the activation of IFN signaling pathways represents an early “dialogue” between motor neurons and astrocytes in response to pathological changes in ALS. © 2011 Wiley‐Liss, Inc.