Abnormal Regenerative Responses and Impaired Axonal Outgrowth after Nerve Crush in TDP-43 Transgenic Mouse Models of Amyotrophic Lateral Sclerosis

• Published in: The Journal of neuroscience Vol. 32; no. 50; pp. 18186 - 18195
• Main Authors: Swarup, Vivek, Audet, Jean-Nicolas, Phaneuf, Daniel, Kriz, Jasna, Julien, Jean-Pierre
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 12.12.2012
• Subjects: Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Axons - metabolism; Axons - pathology; Blotting, Western; Disease Models, Animal; DNA-Binding Proteins - metabolism; 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
• ISSN: 0270-6474; 1529-2401; 1529-2401
• 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.