Abnormal regenerative responses and impaired axonal outgrowth after nerve crush in TDP-43 transgenic mouse models of amyotrophic lateral sclerosis

J Neurosci. 2012 Dec 12;32(50):18186-95. doi: 10.1523/JNEUROSCI.2267-12.2012.


Tar DNA binding protein 43 (TDP-43) mislocalization and aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. Moreover, TDP-43 mRNA was found to be upregulated by ∼2.5-fold in the spinal cord of sporadic ALS subjects. Here we have examined the effects of nerve injury in new transgenic mouse models overexpressing by approximately threefold wild-type or mutant (G348C) TDP-43 species. Four weeks after axonal crush of sciatic nerve, TDP-43 transgenic mice remained paralyzed at the injured limb unlike control mice, which had regained most of their normal mobility. In contrast to normal mice, TDP-43 transgenic mice exhibited sustained elevation of TDP-43 cytoplasmic levels in motor neurons after nerve crush, and the relocalization of TDP-43 to the nucleus was delayed by several weeks. After crush, peripherin and ubiquitin levels remained also significantly elevated in TDP-43 transgenic mice compared with control mice. Analysis of the sciatic nerve at 11 d after nerve crush showed that the number of regenerating axons in the distal portion of the lesion was considerably reduced in TDP-43 transgenic mice, especially in TDP-43(G348C) mice, which exhibited a reduction of ∼40%. In addition, markers of neuroinflammation were detected at much higher levels in TDP-43 transgenic mice. These results suggest that a deregulation of TDP-43 expression in ALS is a phenomenon that can affect the regenerative responses to neuronal injury and regrowth potential of axons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Axons / metabolism
  • Axons / pathology*
  • Blotting, Western
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Crush
  • Nerve Regeneration / physiology*
  • TDP-43 Proteinopathies / metabolism
  • TDP-43 Proteinopathies / pathology


  • DNA-Binding Proteins