Journal
HUMAN MOLECULAR GENETICS
Volume 26, Issue 3, Pages 552-566Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw412
Keywords
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Funding
- Monument Trust Discovery Award from Parkinson's UK
- MRC
- Pfizer
- Wellcome Trust Career Re-Entry Fellowship [WT082260/Z/07/Z]
- Medical Research Council, UK
- Wellcome Trust [090532/Z/09/Z, 092762/Z/10/Z]
- MRC [G0900747 91070]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust
- University of Oxford
- Dementias and Neurodegenerative Diseases Research Network (DeNDRoN)
- Parkinson's UK in England [2581970]
- Parkinson's UK in Wales [2581970]
- Parkinson's UK in Scotland [SC037554]
- NIHR Comprehensive Local Research Network
- Innovative Medicines Initiative Joint Undertaking (IMI JU) [115439]
- European Union's Seventh Framework Programme (FP7)
- EFPIA
- Parkinson's UK [(COAF) J-1403]
- Medical Research Council [MR/L023784/1, MC_PC_15065, MC_PC_16034, MC_EX_MR/N50192X/1, MC_UP_A320_1004, MR/M024962/1, MC_UU_12021/4] Funding Source: researchfish
- Parkinson's UK [J-0901, J-1403] Funding Source: researchfish
- MRC [MR/L023784/1, MC_PC_15065, MC_UP_A320_1004, MR/M024962/1, MC_PC_16034, MC_UU_12021/4, MC_EX_MR/N50192X/1] Funding Source: UKRI
- Wellcome Trust [092762/Z/10/Z] Funding Source: Wellcome Trust
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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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