title: Abnormal regenerative responses and impaired axonal outgrowth after nerve crush in TDP-43 transgenic mouse models of amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Research Centre of CHU of Quebec, Department of Psychiatry and Neuroscience of Laval University, Quebec, Quebec G1V 4G2, Canada.
authors.forename: Vivek
authors.initials: V
authors.lastname: Swarup
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Audet
authors.forename: Daniel
authors.initials: D
authors.lastname: Phaneuf
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D057177:TDP-43 Proteinopathies / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins