title: Direct reprogramming of Huntington's disease patient fibroblasts into neuron-like cells leads to abnormal neurite outgrowth, increased cell death, and aggregate formation.
abstract: Recent advances in trans-differentiation of one type cell to another have made it possible to directly convert Huntington's disease (HD) patient fibroblasts into neurons by modulation of cell-lineage-specific transcription factors or RNA processing. However, this possibility has not been examined. Here, we demonstrate that HD patient-derived fibroblasts can be directly trans-differentiated into neuron-like cells by knockdown of the expression of a single gene encoding the polypyrimidine-tract-binding protein. The directly converted HD neuron-like cells were positive in expression of Tuj1, NeuN, DARPP-32, and γ-aminobutyric acid and exhibited neuritic breakdown, abnormal neuritic branching, increased cell death, and aggregation of mutant huntingtin. These observations indicate that the neuron-like cells directly converted from HD patient fibroblasts recapitulate the major aspects of neuropathological characteristics of HD and thus provide an additional model for understanding the disorder and validation of therapeutic reagents.
authors.affiliation: Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, United States of America.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, The Palade Laboratories Room 231, La Jolla, California, United States of America.
authors.forename: Yuanchao
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, United States of America.
authors.forename: Samantha
authors.initials: S
authors.lastname: Ridley
authors.affiliation: Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, United States of America.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, United States of America.
authors.forename: Khosrow
authors.initials: K
authors.lastname: Rezvani
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, The Palade Laboratories Room 231, La Jolla, California, United States of America.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, United States of America.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Wang
mesh_terms: D016923:Cell Death; D002460:Cell Line; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D016501:Neurites / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000473:pathology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D038941:Polypyrimidine Tract-Binding Protein