Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 2, Pages 829-832Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1314085111
Keywords
neurotoxicity; neurodegeneration; reprogramming
Categories
Funding
- US National Institutes of Health [R01 NS644912-4, RC2 NS69476-01]
- Packard Center for ALS Research Grant [P2ALS]
- Helping Link Foundation
- Swiss National Science Foundation
- Marie Curie Fellowship
- National Institute for Health Research [NF-SI-0512-10082] Funding Source: researchfish
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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.
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