Aicardi-Goutières syndrome is a genetically determined infantile encephalopathy, 
manifesting as progressive microcephaly, psychomotor retardation, and in ∼25% of 
patients, death in early childhood. Aicardi-Goutières syndrome is caused by 
mutations in any of the genes encoding TREX1, RNASEH2-A, -B, -C and SAMHD1, with 
protein dysfunction hypothesized to result in the accumulation of nucleic acids 
within the cell, thus triggering an autoinflammatory response with increased 
interferon-α production. Astrocytes have been identified as a major source of 
interferon-α production in the brains of patients with Aicardi-Goutières 
syndrome. Here, we study the effect of interferon-α treatment on astrocytes 
derived from immortalized human neural stem cells. Chronic interferon-α 
treatment promoted astrocyte activation and a reduction in cell proliferation. 
Moreover, chronic exposure resulted in an alteration of genes and proteins 
involved in the stability of white matter (ATF4, eIF2Bα, cathepsin D, cystatin 
F), an increase of antigen-presenting genes (human leukocyte antigen class I) 
and downregulation of pro-angiogenic factors and other cytokines (vascular 
endothelial growth factor and IL-1). Interestingly, withdrawal of interferon-α 
for 7 days barely reversed these cellular alterations, demonstrating that the 
interferon-α mediated effects persist over time. We confirmed our in vitro 
findings using brain samples from patients with Aicardi-Goutières syndrome. Our 
results support the idea of interferon-α as a key factor in the pathogenesis of 
Aicardi-Goutières syndrome relating to the observed leukodystrophy and 
microangiopathy. Because of the sustained interferon-α effect, even after 
withdrawal, therapeutic targets for Aicardi-Goutières syndrome, and other 
interferon-α-mediated encephalopathies, may include downstream interferon-α 
signalling cascade effectors rather than interferon-α alone.