title: [ALS disease modeling and drug screening using patient-specific iPS cells].
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neuron (MN) loss in the spinal cord leads to progressive paralysis and death. Cytosolic aggregations in ALS MNs are composed of Tar DNA-binding protein-43 (TDP-43). Genetic analysis has identified more than twenty mutations of TDP-43 in ALS cases. Although accumulating evidence provides several hypotheses of disease mechanism, it is still needed to discover effective cure for ALS. We aimed to reveal cellular phenotypes in ALS MNs for identifying a drug-screening target for ALS using patient-specific induced pluripotent stem cells (iPSCs). To generate patient-specific iPSCs, dermal fibroblasts were obtained by biopsy from ALS patients carrying mutant TDP-43. The fibroblasts were reprogrammed by retrovirus or episomal vectors. Disease-specific iPSCs were differentiated into MNs expressing HB9 and SMI-32. Despite short culture period, ALS MNs recapitulated several disease phenotypes including detergent-insoluble TDP-43, shortened neurites and cellular vulnerability that observed in patient and animal models. Anacardic acid treatment reverted those phenotypes. Disease-specific iPSCs might provide a first step for drug-screening platform for ALS using patient-specific iPSCs.
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Egawa
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D048729:Anacardic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D058990:Molecular Targeted Therapy; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D016501:Neurites / Q000473:pathology; D018384:Oxidative Stress
chemical_list: D048729:Anacardic Acids; D004268:DNA-Binding Proteins