Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 2; pp. 829 - 832
• Main Authors: Meyer, Kathrin, Ferraiuolo, Laura, Miranda, Carlos J., Likhite, Shibi, McElroy, Sohyun, Renusch, Samantha, Ditsworth, Dara, Lagier-Tourenne, Clotilde, Smith, Richard A., Ravits, John, Burghes, Arthur H., Shaw, Pamela J., Cleveland, Don W., Kolb, Stephen J., Kaspar, Brian K.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14-01-2014; National Acad Sciences
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - physiopathology; Analysis of Variance; Astrocytes; Astrocytes - cytology; Astrocytes - metabolism; Biological Sciences; Cell Communication; Cell Culture Techniques; Cell Dedifferentiation - physiology; Cell Differentiation - physiology; Coculture techniques; Disease models; DNA Primers - genetics; Fibroblasts; Fibroblasts - cytology; Fluorescent Antibody Technique; Health education; Humans; Medical diagnosis; Models, Biological; Motor neurons; Motor Neurons - metabolism; Motor Neurons - pathology; Neural stem cells; Neural Stem Cells - cytology; Neurons; Neurotoxicity; Pluripotent stem cells; Real-Time Polymerase Chain Reaction; Stem cells; reprogramming; neurodegeneration; neurotoxicity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1314085111

Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration, paralysis, and death. Accurate disease modeling, identifying disease mechanisms, and developing therapeutics is urgently needed. We previously reported motor neuron toxicity through postmortem ALS spinal cord-derived astrocytes. However, these cells can only be harvested after death, and their expansion is limited. We now report a rapid, highly reproducible method to convert adult human fibroblasts from living ALS patients to induced neuronal progenitor cells and subsequent differentiation into astrocytes (i-astrocytes). Non-cell autonomous toxicity to motor neurons is found following coculture of i-astrocytes from familial ALS patients with mutation in superoxide dismutase or hexanucleotide expansion in C9orf72 (ORF 72 on chromosome 9) the two most frequent causes of ALS. Remarkably, i-astrocytes from sporadic ALS patients are as toxic as those with causative mutations, suggesting a common mechanism. Easy production and expansion of i-astrocytes now enables rapid disease modeling and high-throughput drug screening to alleviate astrocyte-derived toxicity.