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Cell. 2018 Sep 6;174(6):1477-1491.e19. doi: 10.1016/j.cell.2018.07.041. Epub 2018 Aug 23.

TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging.

Author information

1
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
2
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Rd., Pudong, 201210 Shanghai, China; University of Chinese Academy of Sciences, 100049 Beijing, China.
3
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Rd., 200032 Shanghai, China.
4
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Rd., Pudong, 201210 Shanghai, China.
5
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
6
Broad Institute, Cambridge, MA 02142, USA.
7
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Rd., Pudong, 201210 Shanghai, China. Electronic address: jyuan@hms.harvard.edu.

Abstract

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.

KEYWORDS:

ALS; FTD; RIPK1; RIPK1-dependent apoptosis; TAK1; TBK1; caspase; necroptosis

PMID:
30146158
PMCID:
PMC6128749
[Available on 2019-09-06]
DOI:
10.1016/j.cell.2018.07.041

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