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

The Journal of Neuroscience, 2012 · DOI: 10.1523/JNEUROSCI.2267-12.2012 · Published: December 12, 2012

Simple Explanation

This study examined the impact of nerve injury in TDP-43 transgenic mouse models, which overexpress either wild-type or mutant TDP-43. The transgenic mice showed paralysis in the injured limb, unlike control mice. The study found that TDP-43 cytoplasmic levels remained elevated in motor neurons of the transgenic mice after nerve crush. The return of TDP-43 to the nucleus was also delayed. The study also found that the number of regenerating axons was reduced in TDP-43 transgenic mice, and markers of neuroinflammation were higher. This suggests that TDP-43 deregulation can affect regenerative responses and axonal regrowth.

Study Duration

42 days

Participants

Nontransgenic, TDP-43WT, TDP-43G348C, GFAP–luciferase, TDP-43 WT/GFAP–luc and TDP-43 G348C/GFAP–luc mice

Evidence Level

Not specified

Key Findings

1
TDP-43 transgenic mice exhibited sustained elevation of TDP-43 cytoplasmic levels in motor neurons after nerve crush, delaying relocalization to the nucleus.
2
The number of regenerating axons in the distal portion of the lesion was considerably reduced in TDP-43 transgenic mice, particularly in TDP-43 G348C mice.
3
Markers of neuroinflammation were detected at much higher levels in TDP-43 transgenic mice compared to control mice after nerve crush.

Research Summary

The study investigated the effects of nerve injury in TDP-43 transgenic mice, which overexpress wild-type or mutant TDP-43, finding that these mice exhibited sustained paralysis, elevated cytoplasmic TDP-43 levels, and delayed TDP-43 relocalization to the nucleus after nerve crush. Analysis of the sciatic nerve showed a considerable reduction in the number of regenerating axons in TDP-43 transgenic mice, especially in TDP-43 G348C mice, along with increased markers of neuroinflammation. These findings suggest that TDP-43 deregulation in ALS can affect regenerative responses to neuronal injury and axonal regrowth potential, impacting the recovery process after nerve damage.

Practical Implications

Understanding ALS Pathogenesis

The study provides insights into how TDP-43 deregulation contributes to impaired nerve regeneration in ALS, enhancing the understanding of disease mechanisms.

Therapeutic Targets

Identifying TDP-43 as a key factor in regenerative responses suggests potential therapeutic targets for promoting nerve repair in ALS and other neurodegenerative conditions.

Biomarker Development

The sustained elevation of cytoplasmic TDP-43 and other markers could be explored as biomarkers for assessing nerve damage and regenerative capacity in ALS patients.

Study Limitations

1
The study is limited to mouse models, and findings may not directly translate to human ALS patients.
2
The study focuses on nerve crush injury, which may not fully represent the complex pathology of ALS.
3
Further research is needed to elucidate the precise molecular mechanisms by which TDP-43 deregulation impairs axonal regeneration.

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