Related Experiment Video

Updated: Dec 23, 2025

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System
08:15

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System

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

Daichao Xu1, Taijie Jin2, Hong Zhu1

  • 1Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.

Cell
|August 28, 2018
PubMed

Insights

Aging exacerbates neurodegeneration by reducing TAK1, which activates RIPK1. This interaction with genetic factors like TBK1 loss promotes amyotrophic lateral sclerosis and frontotemporal dementia.

Area of Science:

  • Neuroscience
  • Genetics
  • Aging Research

Background:

  • Aging is a primary risk factor for neurodegenerative diseases.
  • The interplay between aging and genetic predispositions in neurodegeneration remains unclear.
  • TBK1 mutations are a known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Purpose of the Study:

  • To investigate how partial loss of TBK1 function interacts with aging to drive neurodegeneration.
  • To elucidate the role of RIPK1 and TAK1 in age-dependent neurodegenerative processes.

Main Methods:

  • Utilized Tbk1+/- mouse models to study age-dependent neurodegeneration.
  • Assessed the expression levels of RIPK1 inhibitors (TBK1 and TAK1) in aging brains.
  • Investigated the impact of RIPK1 inhibition on ALS/FTD hallmarks in Tbk1+/- mice.

Main Results:

  • TBK1 acts as an endogenous inhibitor of RIPK1.
  • Aging human brains show decreased expression of TAK1, another RIPK1 inhibitor.
  • Reduced myeloid TAK1 expression in Tbk1+/- mice promoted neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss, and behavioral deficits.
  • RIPK1 inhibition successfully blocked these ALS/FTD hallmarks.

Conclusions:

  • Aging facilitates RIPK1 activation by reducing TAK1 expression.
  • This age-related RIPK1 activation cooperates with genetic risk factors (e.g., TBK1 loss) to promote ALS/FTD onset.
  • Targeting RIPK1 may offer therapeutic strategies for age-related neurodegenerative diseases.
Keywords:
ALSFTDRIPK1RIPK1-dependent apoptosisTAK1TBK1caspasenecroptosis

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