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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aging
  • Animals
  • Apoptosis* / drug effects
  • Axons / metabolism
  • Behavior, Animal
  • Brain / cytology
  • Brain / metabolism
  • Cells, Cultured
  • Humans
  • I-kappa B Kinase / metabolism
  • Mice
  • Mice, Knockout
  • Microglia / cytology
  • Microglia / drug effects
  • Microglia / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Spinal Cord / metabolism
  • Staurosporine / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Tumor Necrosis Factor-alpha
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • I-kappa B Kinase
  • Staurosporine