TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging.
Cell
; 174(6): 1477-1491.e19, 2018 09 06.
Article
em En
| MEDLINE
| ID: mdl-30146158
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
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Apoptose
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Proteína Serina-Treonina Quinases de Interação com Receptores
Tipo de estudo:
Risk_factors_studies
Limite:
Adult
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Aged
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Animals
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article