title: Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS.
abstract: 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.
authors.affiliation: The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Meyer
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Miranda
authors.forename: Shibi
authors.initials: S
authors.lastname: Likhite
authors.forename: Sohyun
authors.initials: S
authors.lastname: McElroy
authors.forename: Samantha
authors.initials: S
authors.lastname: Renusch
authors.forename: Dara
authors.initials: D
authors.lastname: Ditsworth
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.forename: Richard A
authors.initials: RA
authors.lastname: Smith
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Burghes
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kolb
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000704:Analysis of Variance; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D002450:Cell Communication; D018929:Cell Culture Techniques; D054337:Cell Dedifferentiation / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000166:cytology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers
keywords: neurodegeneration; neurotoxicity; reprogramming