title: Rescue of an in vitro neuron phenotype identified in Niemann-Pick disease, type C1 induced pluripotent stem cell-derived neurons by modulating the WNT pathway and calcium signaling.
abstract: Niemann-Pick disease, type C1 (NPC1) is a familial disorder that has devastating consequences on postnatal development with multisystem effects, including neurodegeneration. There is no Food and Drug Administration-approved treatment option for NPC1; however, several potentially therapeutic compounds have been identified in assays using yeast, rodent models, and NPC1 human fibroblasts. Although these discoveries were made in fibroblasts from NPC1 subjects and were in some instances validated in animal models of the disease, testing these drugs on a cell type more relevant for NPC1 neurological disease would greatly facilitate both study of the disease and identification of more relevant therapeutic compounds. Toward this goal, we have generated an induced pluripotent stem cell line from a subject homozygous for the most frequent NPC1 mutation (p.I1061T) and subsequently created a stable line of neural stem cells (NSCs). These NSCs were then used to create neurons as an appropriate disease model. NPC1 neurons display a premature cell death phenotype, and gene expression analysis of these cells suggests dysfunction of important signaling pathways, including calcium and WNT. The clear readout from these cells makes them ideal candidates for high-throughput screening and will be a valuable tool to better understand the development of NPC1 in neural cells, as well as to develop better therapeutic options for NPC1.
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NeuroTherapeutics Development Unit, National Institute for Neurological Diseases and Stroke, Genetic Disease Research Branch, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute for Child Health and Human Development, and Center for Regenerative Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors: Anastasia G
authors: AG
authors: Efthymiou
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NeuroTherapeutics Development Unit, National Institute for Neurological Diseases and Stroke, Genetic Disease Research Branch, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute for Child Health and Human Development, and Center for Regenerative Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors: Joe
authors: J
authors: Steiner
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NeuroTherapeutics Development Unit, National Institute for Neurological Diseases and Stroke, Genetic Disease Research Branch, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute for Child Health and Human Development, and Center for Regenerative Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors: William J
authors: WJ
authors: Pavan
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NeuroTherapeutics Development Unit, National Institute for Neurological Diseases and Stroke, Genetic Disease Research Branch, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute for Child Health and Human Development, and Center for Regenerative Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors: Stephen
authors: S
authors: Wincovitch
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NeuroTherapeutics Development Unit, National Institute for Neurological Diseases and Stroke, Genetic Disease Research Branch, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute for Child Health and Human Development, and Center for Regenerative Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors: Denise M
authors: DM
authors: Larson
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NeuroTherapeutics Development Unit, National Institute for Neurological Diseases and Stroke, Genetic Disease Research Branch, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute for Child Health and Human Development, and Center for Regenerative Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors: Forbes D
authors: FD
authors: Porter
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NeuroTherapeutics Development Unit, National Institute for Neurological Diseases and Stroke, Genetic Disease Research Branch, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute for Child Health and Human Development, and Center for Regenerative Medicine, National Institutes of Health, Bethesda, Maryland, USA.
authors: Mahendra S
authors: MS
authors: Rao
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NeuroTherapeutics Development Unit, National Institute for Neurological Diseases and Stroke, Genetic Disease Research Branch, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute for Child Health and Human Development, and Center for Regenerative Medicine, National Institutes of Health, Bethesda, Maryland, USA malikn@mail.nih.gov.
authors: Nasir
authors: N
authors: Malik
mesh_terms: D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D060449:Wnt Signaling Pathway
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein
keywords: Calcium signaling; Disease modeling; Neural stem cells; Niemann-pick disease, type C1; WNT signaling
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