Research Models

TDP-43 (WT) (Julien model)

Synonyms: Wild-type TDP-43

Species: Mouse
Genes: TARDBP
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: Transgene injected into C3H x C57Bl/6 embryos. Founders crossed with C57Bl/6.
Availability: Not available: extinct

Summary

These transgenic mice, which are now extinct, overexpressed wild-type human TDP-43. They developed motor and cognitive deficits relevant to ALS/FTD, along with pertinent neuropathology, including gliosis and denervation of neuromuscular junctions. Phenotypes were generally milder than what had been observed in mice overexpressing mutant TDP-43 (e.g., TDP-43 A315T and TDP-43 G348C) (Swarup et al., 2011).

In contrast to other TDP-43 transgenics using strong promoters, this model used the endogenous human TDP-43 promoter, resulting in relatively modest expression levels. In the brain, mRNA levels of TDP-43 were about threefold higher than endogenous mouse levels. Human TDP-43 protein was abundantly expressed in the brain, spinal cord, and muscle, with lower levels in the liver and kidney, mimicking endogenous expression patterns.

Neuronal TDP-43 protein was primarily nuclear. This nuclear localization contrasts with observations reported in mice overexpressing mutant TDP-43 (i.e. TDP-43 A315T and TDP-43 G348C), which accumulate cytoplasmic TDP-43 in neurons by 10 months of age.

Neuronal loss has not been reported in these mice and axon numbers were preserved. However, at the neuromuscular junction (NMJ) some denervation was apparent by 10 months of age (about 5 percent full denervation and another 20 percent partial denervation). Gliosis was prominent in these mice. Microgliosis and astrogliosis occurred by three months of age in the spinal cord and increased markedly by 10 months of age.

Behaviorally, these mice showed both motor and cognitive deficits. They exhibited deficits in the passive-avoidance test at seven months of age and in the Barnes maze at 10 months, indicating deficits in contextual and spatial memory, respectively. Around this same age (i.e., 42 weeks), the mice developed difficulties on the accelerating Rotarod. Of note, motor impairment was reported at slightly younger ages in mice overexpressing mutant TDP-43, at 36 and 38 weeks (Swarup et al., 2011).

Compared with non-Tg mice, TDP-43(WT) transgenics recovered more slowly from nerve injury (Swarup et al., 2012). Following crush injury to the sciatic nerve, three-month-old TDP-43 (WT) mice recovered motility slowly, and their recovery was incomplete. Eleven days after injury, they had fewer regenerating axons at the injury site and increased neuroinflammation.

Data on this page refer to hemizygous mice.

Modification Details

These mice express full-length, wild-type, human TDP-43 driven by the endogenous human promoter.

Related Strains

TDP-43 (G348C)

TDP-43 (A315T)

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions

No Data

  • Muscle Atrophy
  • Body Weight
  • Premature Death

Cortical Neuron Loss

Not observed.

Lower Motor Neuron Loss

Not observed.

Cytoplasmic Inclusions

Primarily nuclear localization of human TDP-43.

Gliosis

Gliosis, both microgliosis and astrogliosis, occur early in the brain and spinal cord. Reactive glia were detected as early as 3 months of age, with more by 10 months.

NMJ Abnormalities

Some NMJ denervation was observed by 10 months of age. About 5% of NMJs at the gastrocnemius muscle were denervated, with another 20 percent partially denervated.

Muscle Atrophy

No data.

Motor Impairment

Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.

Body Weight

No data.

Premature Death

No data.

COMMENTS / QUESTIONS

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References

Research Models Citations

  1. TDP-43 (G348C)
  2. TDP-43 (A315T)

Paper Citations

  1. . Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain. 2011 Sep;134(Pt 9):2610-26. Epub 2011 Jul 13 PubMed.
  2. . 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. PubMed.

Further Reading

No Available Further Reading