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Status |
Public on Apr 15, 2024 |
Title |
Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, that we further characterized by single nucleus RNA-sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.
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Overall design |
Analysis of post-mortem human brain samples and iPSC neurons genomic information
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Web link |
https://doi.org/10.1016/j.stem.2024.03.013
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Contributor(s) |
Al-Dalahmah O, Lam M, McInvale JJ, Qu W, Nguyen T, Mun J, Kwon S, Ifediora N, Mahajan A, Humala N, Winters T, Angeles E, Jakubiak KA, Kühn R, Kim YA, De Rosa MC, Doege C, Paryani F, Flowers X, Dovas A, Mela A, Lu H, DeTure MA, Vonsattel JP, Wszolek ZK, Dickson DW, Kuhlmann T, Zaehres H, Schöler HR, Sproul AA, Siegelin MD, De Jager PL, Goldman JE, Menon V, Canoll P, Hargus G |
Citation(s) |
38626772 |
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Submission date |
Apr 25, 2023 |
Last update date |
Jul 15, 2024 |
Contact name |
Osama Al Dalahmah |
E-mail(s) |
oa2298@cumc.columbia.edu
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Organization name |
Columbia University Irving Medical Center
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Department |
Pathology & Cell Biology
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Street address |
622 West 168th Street
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City |
New York |
State/province |
NY |
ZIP/Postal code |
10032 |
Country |
USA |
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Platforms (1) |
GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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Samples (21)
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GSM7225757 |
Postmortem human brain, FTD, HO008 |
GSM7225758 |
Postmortem human brain, FTD, HO010 |
GSM7225759 |
Postmortem human brain, FTD, HO012 |
GSM7225760 |
Postmortem human brain, Ctrl , HO002 |
GSM7225761 |
Postmortem human brain, Ctrl , GO003 |
GSM7225762 |
Postmortem human brain, Ctrl , GO005 |
GSM7225763 |
Postmortem human brain, Ctrl , HO007 |
GSM7225764 |
Postmortem human brain, Ctrl , HO009 |
GSM7225765 |
Postmortem human brain, Ctrl , HO011 |
GSM7225766 |
Postmortem human brain, Ctrl , HO013 |
GSM7225767 |
iPSC-derived neural graft, Ctrl , GF010 |
GSM7225768 |
iPSC-derived neural graft, Ctrl , GF012 |
GSM7225769 |
iPSC-derived neural graft, Ctrl , GF014 |
GSM7225770 |
iPSC-derived neural graft, Ctrl , GF016 |
GSM7225771 |
iPSC-derived neural graft, FTD, GF011 |
GSM7225772 |
iPSC-derived neural graft, FTD, GF013 |
GSM7225773 |
iPSC-derived neural graft, FTD, GF015 |
GSM7225774 |
iPSC-derived neural graft, FTD, GF017 |
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This SubSeries is part of SuperSeries: |
GSE230520 |
Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons |
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Relations |
BioProject |
PRJNA961689 |
Supplementary file |
Size |
Download |
File type/resource |
GSE230519_RAW.tar |
291.8 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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