Microtubule disruption upon CNS damage triggers mitotic entry via TNF signaling activation

Cell Rep. 2021 Jul 6;36(1):109325. doi: 10.1016/j.celrep.2021.109325.

Abstract

Repair after traumatic injury often starts with mitotic activation around the lesion edges. Early midline cells in the Drosophila embryonic CNS can enter into division following the traumatic disruption of microtubules. We demonstrate that microtubule disruption activates non-canonical TNF signaling by phosphorylation of TGF-β activated kinase 1 (Tak1) and its target IkappaB kinase (Ik2), culminating in Dorsal/NfkappaB nuclear translocation and Jra/Jun expression. Tak1 and Ik2 are necessary for the damaged-induced divisions. Microtubule disruption caused by Tau accumulation is also reported in Alzheimer's disease (AD). Human Tau expression in Drosophila midline cells is sufficient to induce Tak1 phosphorylation, Dorsal and Jra/Jun expression, and entry into mitosis. Interestingly, activation of Tak1 and Tank binding kinase 1 (Tbk1), the human Ik2 ortholog, and NfkappaB upregulation are observed in AD brains.

Keywords: Alzheimer's disease; Drosophila; Tak1; Tbk1; microtubules; mitosis; neuronal damage; tissue damage; ventral midline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology
  • Animals
  • Brain / pathology
  • Cell Death
  • Central Nervous System / pathology*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / embryology
  • Drosophila melanogaster / metabolism*
  • Embryonic Development
  • Humans
  • Microtubules / metabolism
  • Microtubules / pathology*
  • Mitosis*
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Isoforms / metabolism
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / metabolism*
  • tau Proteins / metabolism

Substances

  • Drosophila Proteins
  • NF-kappa B
  • Protein Isoforms
  • Tumor Necrosis Factor-alpha
  • tau Proteins