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Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson's disease.
Sandor, Cynthia; Robertson, Paul; Lang, Charmaine; Heger, Andreas; Booth, Heather; Vowles, Jane; Witty, Lorna; Bowden, Rory; Hu, Michele; Cowley, Sally A; Wade-Martins, Richard; Webber, Caleb.
Afiliação
  • Sandor C; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
  • Robertson P; MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
  • Lang C; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
  • Heger A; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
  • Booth H; MRC Computational Genomics Analysis and Training Program, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
  • Vowles J; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
  • Witty L; James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
  • Bowden R; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Hu M; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Cowley SA; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
  • Wade-Martins R; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
  • Webber C; James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Hum Mol Genet ; 26(3): 552-566, 2017 02 01.
Article em En | MEDLINE | ID: mdl-28096185
ABSTRACT
While induced pluripotent stem cell (iPSC) technologies enable the study of inaccessible patient cell types, cellular heterogeneity can confound the comparison of gene expression profiles between iPSC-derived cell lines. Here, we purified iPSC-derived human dopaminergic neurons (DaNs) using the intracellular marker, tyrosine hydroxylase. Once purified, the transcriptomic profiles of iPSC-derived DaNs appear remarkably similar to profiles obtained from mature post-mortem DaNs. Comparison of the profiles of purified iPSC-derived DaNs derived from Parkinson's disease (PD) patients carrying LRRK2 G2019S variants to controls identified significant functional convergence amongst differentially-expressed (DE) genes. The PD LRRK2-G2019S associated profile was positively matched with expression changes induced by the Parkinsonian neurotoxin rotenone and opposed by those induced by clioquinol, a compound with demonstrated therapeutic efficacy in multiple PD models. No functional convergence amongst DE genes was observed following a similar comparison using non-purified iPSC-derived DaN-containing populations, with cellular heterogeneity appearing a greater confound than genotypic background.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Células-Tronco Pluripotentes Induzidas / Transcriptoma / Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina Limite: Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Reino Unido
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Células-Tronco Pluripotentes Induzidas / Transcriptoma / Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina Limite: Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Reino Unido