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| Status |
Public on Jul 04, 2018 |
| Title |
TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here we investigate how partial loss-of-function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.
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| Overall design |
mRNA profiles of primary microglia derived from 2-day old wild type (WT), Tbk1+/-, Tbk1+/-;Ripk1D138N/D138N, Tak1ΔM/+, Tbk1+/-;Tak1ΔM/+ and Tbk1+/-;Tak1ΔM/+;RIpk1D138N/+ mice were generated by bulk RNA sequencing, in triplicate.
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| Contributor(s) |
Xu D, Yuan J |
| Citation(s) |
30146158 |
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| Submission date |
Jul 03, 2018 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Daichao Xu |
| E-mail(s) |
Daichao_Xu@hms.harvard.edu
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| Phone |
7816288605
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| Organization name |
Harvard Medical School
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| Department |
Cell Biology
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| Lab |
Junying Yuan
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| Street address |
240 Longwood Ave.
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA479506 |
| SRA |
SRP151942 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE116613_processed_data_All_in_one.txt.gz |
715.6 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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