title: Amyotrophic lateral sclerosis models derived from human embryonic stem cells with different superoxide dismutase 1 mutations exhibit differential drug responses.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron (MN) disease. The gene encoding superoxide dismutase 1 (SOD1) is a causative element of familial ALS. Animal ALS models involving SOD1 gene mutations are widely used to study the underlying mechanisms of disease and facilitate drug discovery. Unfortunately, most drug candidates have failed in clinical trials, potentially due to species differences among rodents and humans. It is unclear, however, whether there are different responses to drugs among the causative genes of ALS or their associated mutations. In this study, to evaluate different SOD1 mutations, we generated SOD1-ALS models derived from human embryonic stem cells with identical genetic backgrounds, except for the overexpression of mutant variants of SOD1. The overexpression of mutant SOD1 did not affect pluripotency or MN differentiation. However, mutation-dependent reductions in neurite length were observed in MNs. Moreover, experiments investigating the effects of specific compounds revealed that each ALS model displayed different responses with respect to MN neurite length. These results suggest that SOD1 mutations could be classified based the response of MNs to drug treatment. This classification could be useful for the development of mutant-specific strategies for drug discovery and clinical trials.
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan; Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Tooi
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan; Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Nakatsuji
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan. Electronic address: kaiba@icems.kyoto-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aiba
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000066449:Human Embryonic Stem Cells; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects*; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Drug response; Human embryonic stem cell; Motor neuron; SOD1