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| Status |
Public on Oct 27, 2022 |
| Title |
Single nuclei RNAseq analysis of HD mouse model and human brain reveals impaired 1 oligodendrocyte maturation and potential causal regulators |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
A challenge in treating Huntington’s disease (HD) is the complexity of affected brain regions and cell types. We carried out a systematic analysis of cell type-specific changes in cortex and striatum from R6/2 mice at 8 and 12w, and in three regions of human HD post-mortem tissue using single nucleus RNA sequencing. We discovered major expression changes in oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs), suggesting that many OLs were arrested in an immature state. Causal gene network analysis implicates PRKCE and SWI/SNF in abnormal OL maturation. PRKCE protein was dramatically decreased in mouse and human HD, and its regulator, diacylglycerol lipids, were decreased in human HD at very early stages. ATACseq of mouse glia showed increased accessibility of sites regulated by SWI/SNF subunit Smarca4 in HD, further implicating Prkce-SWI/SNF. We identified differences between 8w and 12w mice in the induction of OPC 37 maturation, with 12w mice most similar to human. Disrupted cell-to-cell signaling between medium spiny neurons and OL, that may contribute to neuronal dysfunction, was identified in both human HD and R6/2 mice using ligand-receptor analysis. These findings reveal novel insights into OL pathology that spans multiple brain regions in humans and mice and suggest therapeutic strategies.
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| Overall design |
Examination of snRNAseq profiles of human glial and neuronal cells from three different postmortem brain regions (cingulate cortex, caudate nucleus, and nucleus accumbens) from seven Huntington disease and six control donors
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| Contributor(s) |
Al-Dalahmah O |
| Citation(s) |
36543778 |
| |
| Submission date |
Jul 27, 2021 |
| Last update date |
Jan 11, 2023 |
| Contact name |
Osama Al-Dalahmah |
| E-mail(s) |
osama.aldalahmah@gmail.com, oa2298@cumc.columbia.edu
|
| Organization name |
Columbia University
|
| Department |
Pathology and Cell Biology
|
| Street address |
630 West, 168th Street
|
| 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 (32)
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| Relations |
| BioProject |
PRJNA750119 |
| SRA |
SRP330306 |
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