title: Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson's disease.
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.
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.|MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sandor
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Robertson
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
authors.forename: Charmaine
authors.initials: C
authors.lastname: Lang
authors.affiliation: MRC Computational Genomics Analysis and Training Program, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heger
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Booth
authors.affiliation: James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Vowles
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Lorna
authors.initials: L
authors.lastname: Witty
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Rory
authors.initials: R
authors.lastname: Bowden
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.|Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Hu
authors.affiliation: James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Cowley
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
authors.affiliation: Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.|MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Caleb
authors.initials: C
authors.lastname: Webber
mesh_terms: D001344:Autopsy; D002478:Cells, Cultured; D007464:Clioquinol / Q000008:administration & dosage; D004298:Dopamine / Q000235:genetics; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012402:Rotenone / Q000378:metabolism / Q000633:toxicity; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*
chemical_list: D012402:Rotenone; D007464:Clioquinol; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D004298:Dopamine