Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury

Brain Res. 2009 Jan 16;1249:202-11. doi: 10.1016/j.brainres.2008.10.021. Epub 2008 Nov 1.

Abstract

We have performed sciatic axotomies in adult C57BL/6 mice and observed TDP-43 and progranulin (PGRN) expression patterns over 28 days. TDP-43 expression was markedly upregulated in axotomized motor neurons, with prominent cytosolic immunoreactivity becoming maximal by post-injury day 7 and returning to baseline levels by post-injury day 28. Increased TDP-43 expression was confirmed by western blot. TDP-43 mRNA expression was also increased. This was inversely correlated with neuronal PGRN expression which was clearly reduced by day 7 with a return to baseline by post-injury day 28. In contrast, microglial PGRN expression was dramatically increased, and correlated with the inflammatory response to axotomy. Cytosolic TDP-43 colocalized with Staufen and TIA-1, markers for RNA transport and stress granules respectively. We did not observe colocalization of TDP-43 or PGRN with degradative granules (P-bodies) or activated caspase 3. These results indicate that TDP-43 expression is altered in response to neuronal injury and that normal expression is restored following recovery. These findings suggest that the upregulation of TDP-43 expression with prominent cytosolic localization in motor neurons injured by degenerative processes such as ALS may actually represent an appropriate response to neuronal injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Axotomy*
  • Caspase 3 / metabolism
  • Cytosol / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Granulins
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Microscopy, Confocal
  • Motor Neurons / metabolism*
  • Progranulins
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism
  • Sciatic Nerve / injuries
  • Sciatic Nerve / physiopathology
  • Spinal Cord / metabolism*
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Stau1 protein, mouse
  • Casp3 protein, mouse
  • Caspase 3