Research Models

TDP-43 (A315T)

Species: Mouse
Genes: TARDBP
Mutations: TARDBP A315T
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: Transgene injected into C3H x C57Bl/6 embryos and then crossed with C57Bl/6.
Availability: Available through Jean-Pierre Julien

Summary

Among the first wave of TDP-43 transgenics, this model uses the endogenous human promoter to express moderate levels of TDP-43. Expression in the brain was about threefold higher than levels of endogenous mouse TDP-43 mRNA. As they age, these mice develop neuropathology and behavioral deficits relevant to ALS/FTD, including cytoplasmic TDP-43 inclusions, neuroinflammation, axonal pathology, and cognitive and motor impairment. They do not develop neuronal loss or paralysis (Swarup et al., 2011).

Despite relatively moderate expression of human TDP-43, these mice accumulate cytoplasmic TDP-43 in the brain and spinal cord, including TDP-43 aggregates. These inclusions are not present at three months of age. Many of these inclusions co-localize with ubiquitin, although TDP-43 itself is not thought to be ubiquitinated. The cytotoxic 25 kDA C-terminal fragment of TDP-43 also increased in an age-dependent manner in both the brain and spinal cord.

Evidence of cytoskeletal abnormalities was observed in the brain and spinal cord, including aggregates of the intermediate filament peripherin, a hallmark of degenerating motor neurons in ALS. However, even at advanced ages, overt neuronal loss was absent, as was axonal loss in the ventral root. However, differences in axon caliber were observed in 10-month-old transgenics compared to non-Tg littermates.

Neuroinflammation was an early and prominent feature in these mice, including astrogliosis and microgliosis in presymptomatic mice (e.g., at three months). Gliosis further increased between three and 10 months of age.

Behaviorally, these mice develop age-dependent cognitive deficits, including learning and memory problems. In the passive avoidance test, a measure of contextual memory, behavior is comparable to wild-type littermates until seven months of age, at which time the TDP-43 A315T mice display severe impairment. Around the same time (e.g., 38 weeks of age), they also develop motor deficits, specifically impaired performance on the Rotarod compared with non-Tg littermates.

Data on this page refer to hemizygous mice.

Modification Details

These mice overexpress full-length human TDP-43 with the A315T mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human promoter.

Availability

Available through Jean-Pierre Julien.

Related Strains

TDP-43 (WT)

TDP-43 (G348C)

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
  • Premature Death

No Data

  • NMJ Abnormalities
  • Muscle Atrophy
  • Body Weight

Cortical Neuron Loss

Not observed.

Lower Motor Neuron Loss

Not observed.

Cytoplasmic Inclusions

Cytoplasmic accumulation of TDP-43 was observed by 10 months of age in the spinal cord. Furthermore, cytoplasmic aggregates were observed and often co-localized with ubiquitin. These inclusions are not detected at three months of age.

Gliosis

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

NMJ Abnormalities

Unknown.

Muscle Atrophy

Unknown.

Motor Impairment

At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.

Body Weight

Unknown.

Premature Death

Not observed.

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References

Research Models Citations

  1. TDP-43 (G348C)

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.

Other Citations

  1. Jean-Pierre Julien

Further Reading