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Hum Mol Genet. 2017 Feb 1;26(3):552-566. doi: 10.1093/hmg/ddw412.

Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson's disease.

Author information

1
Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, Oxford, UK.
2
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
3
MRC Computational Genomics Analysis and Training Program, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
4
James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
5
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
6
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

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.

PMID:
28096185
PMCID:
PMC5409122
DOI:
10.1093/hmg/ddw412
[Indexed for MEDLINE]
Free PMC Article

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