Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice

J Exp Med. 2019 Feb 4;216(2):267-278. doi: 10.1084/jem.20180729. Epub 2019 Jan 11.


Heterozygous loss-of-function mutations of TANK-binding kinase 1 (TBK1 ) cause familial ALS, yet downstream mechanisms of TBK1 mutations remained elusive. TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous Tbk1 deletion alone does not lead to signs of motoneuron degeneration or disturbed autophagy in mice during a 200-d observation period. Surprisingly, however, hemizygous deletion of Tbk1 inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked SOD1G93A , which represents a "second hit" that induces both neuroinflammation and proteostatic dysregulation. At the early stage, heterozygous Tbk1 deletion impairs autophagy in motoneurons and prepones both the clinical onset and muscular denervation in SOD1G93A/Tbk1+/- mice. At the late disease stage, however, it significantly alleviates microglial neuroinflammation, decelerates disease progression, and extends survival. Our results indicate a profound effect of TBK1 on brain inflammatory cells under pro-inflammatory conditions and point to a complex, two-edged role of TBK1 in SOD1-linked ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Amyotrophic Lateral Sclerosis* / pathology
  • Animals
  • Autophagic Cell Death / genetics
  • Brain* / metabolism
  • Brain* / pathology
  • Gene Deletion*
  • Loss of Function Mutation
  • Mice
  • Mice, Knockout
  • Microglia / metabolism
  • Microglia / pathology
  • Motor Neurons* / metabolism
  • Motor Neurons* / pathology
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1 / genetics
  • Superoxide Dismutase-1 / metabolism


  • SOD1 G93A protein
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases