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GEO help: Mouse over screen elements for information. |
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| Status |
Public on May 10, 2022 |
| Title |
Neurons burdened by DNA double strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
DNA double strand breaks (DSBs) are linked to neurodegeneration and senescence. However, it is not clear how DSB-bearing neurons influence neuroinflammation associated with neurodegeneration. Here, we characterize DSB-bearing neurons from the CK-p25 mouse model of neurodegeneration using single-nucleus, bulk, and spatial transcriptomic techniques. DSB-bearing neurons enter a late-stage DNA damage response marked by NFκB-activated senescent and antiviral immune pathways. In humans, Alzheimer’s disease pathology is significantly associated with immune activation in excitatory neurons. Spatial transcriptomics reveal that regions of CK-p25 brain tissue dense with DSB-bearing neurons harbor signatures of inflammatory microglia, which is ameliorated by NFκB knock-down in neurons. Inhibition of NFκB in DSB-bearing neurons also reduces microglia activation in organotypic mouse brain slice culture. In conclusion, DSBs activate immune pathways in neurons, which in turn adopt a senescence-associated secretory phenotype to elicit microglia activation. These findings highlight a novel role for neurons in the mechanism of disease-associated neuroinflammation.
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| Overall design |
We used the CK-p25 mouse model of neurodegeneration to study the role of DSB-bearing neurons in neurodegeneration. Two male CK-p25 mice and two male CK mice were used for bulk RNA-sequencing. Stage 1, Stage 2, Baseline neurons, and Glia (so termed by NeuN and gH2AX imunoreactivity) were sorted from each mouse using FANS, then sequenced. For single-nucleus RNA-seq, Stage 1, Stage 2, Baseline neurons, and Glia were sorted and sequenced from three CK-p25 animals and three CK control littermates 1-week and 2-weeks after p25 induction. A total of 1,357 single nucleus libraries were prepared using SMARTseq2 chemistry. Three biological replicates each were used for bulk RNA-seq of etoposide-treated primary neurons (50um, 6hours), and dmso-control primary neurons. Three biological replicates each were used for bulk RNA-seq of FAN-sorted microglia nuclei from CK-p25 p65kd, CK-p25 Scramble, and CK Control PBS mice. Microglia nuclei were sorted based on PU.1 immunoreactivity.
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| Contributor(s) |
Tsai L, Welch GM, Su Q, Pfenning AR, Boix CA, Kellis M, Schmauch E |
| Citation(s) |
36170369 |
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| Submission date |
May 11, 2021 |
| Last update date |
Nov 29, 2022 |
| Contact name |
Li-Huei Tsai |
| E-mail(s) |
lhtsai_geo@hotmail.com
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| Phone |
617-324-1660
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| Organization name |
MIT
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| Department |
Picower Institute for Learning and Memory
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| Lab |
Li-Huei Tsai
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| Street address |
77 Mass Ave # 46-4235
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| City |
Cambridge |
| State/province |
Massachusetts |
| ZIP/Postal code |
02139 |
| Country |
USA |
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| Platforms (3) |
| GPL16417 |
Illumina MiSeq (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (47)
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| Relations |
| BioProject |
PRJNA729044 |
| SRA |
SRP319378 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE174265_RAW.tar |
164.8 Mb |
(http)(custom) |
TAR (of JSON, TIFF) |
| GSE174265_annotation_capture_areas.tsv.gz |
363.9 Kb |
(ftp)(http) |
TSV |
| GSE174265_bulk_RNA_CKp25_all_count_matrix.txt.gz |
1.6 Mb |
(ftp)(http) |
TXT |
| GSE174265_etp_count_matrix.txt.gz |
701.9 Kb |
(ftp)(http) |
TXT |
| GSE174265_etp_metadata.txt.gz |
92 b |
(ftp)(http) |
TXT |
| GSE174265_normalized_counts.tsv.gz |
125.1 Mb |
(ftp)(http) |
TSV |
| GSE174265_pu1_count_matrix.txt.gz |
624.4 Kb |
(ftp)(http) |
TXT |
| GSE174265_pu1_metadata.txt.gz |
176 b |
(ftp)(http) |
TXT |
| GSE174265_raw_counts.tsv.gz |
110.3 Mb |
(ftp)(http) |
TSV |
| GSE174265_scRNA_CKP25_count_matrix_metadata_all.tsv.gz |
8.5 Kb |
(ftp)(http) |
TSV |
| GSE174265_scRNA_CKp25_count_matrix_all.tsv.gz |
3.3 Mb |
(ftp)(http) |
TSV |
| GSE174265_scRNA_CKp25_count_matrix_columnnames_all.tsv.gz |
2.9 Kb |
(ftp)(http) |
TSV |
| GSE174265_scRNA_CKp25_count_matrix_metadata_QCd_only.tsv.gz |
50.7 Kb |
(ftp)(http) |
TSV |
| GSE174265_scRNA_CKp25_count_matrix_rowname_symb_all.tsv.gz |
178.7 Kb |
(ftp)(http) |
TSV |
| GSE174265_visium_metadata.xlsx |
9.0 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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