Research Models

TARDBP (A315T) (hybrid)

Synonyms: Baloh’s TDP-43, C57BL/6-CBA TDP-43 A315T

Species: Mouse
Genes: TARDBP
Mutations: TARDBP A315T
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Genetic Background: The Prp-TDP43A315T transgene was introduced into oocytes from C57BL/6J x CBA mice.
Availability: No longer available on a C57BL/6J x CBA background

Summary

In 2009, Robert Baloh and colleagues reported a transgenic mouse model of ALS based on the overexpression of mutant TARDBP (TDP-43) (Wegorzewska et al., 2009). These mice developed several features of ALS, including motor impairment, degeneration of cortical and spinal motor neurons, cytoplasmic aggregates of ubiquitinated proteins, and premature death. Notably absent was cytoplasmic deposition of TDP-43 protein.

This page describes the TARDBP (A315T) mouse on a mixed genetic background, as originally reported in 2009. These mice are no longer available on the C57BL/6J x CBA background. A congenic line was subsequently generated by crossing the hybrid line to C57BL/6J mice. The congenic mice, which are available through the Jackson Lab (see below), were found to die prematurely from bowel obstruction (Hatzipetros et al., 2013; Guo et al., 2012). Their severe gastrointestinal dysfunction affects their use and maintenance, as well as the interpretation of the phenotypes they exhibit.

The original animals, TARDBP (A315T) (hybrid),  appear normal until about three months of age. At that time, they began to show gait abnormalities. By four to five months they exhibit what was described as a “swimming gait” because they were unable to hold their bodies off the ground. On average, they survived about five months (154 ± 19 days), before dying or being euthanized. It was not reported if the survival analysis included males, females, or both.

By end-stage, the mice were reported to develop both upper and lower and motor neuron loss. Specifically, neuronal loss was observed in layer 5 of the motor cortex as well as in lumbar regions of the region of the spinal cord (L3-L5). About 20 percent of neurons in the spinal cord were lost at end-stage. Although cytoplasmic TDP-43 deposition was notably absent, aggregates of ubiquitinated proteins accumulated in specific neuronal populations, including layer 5 neurons in the frontal cortex, as well as in spinal motor neurons.

Transgene expression in this model is robust, with approximately threefold more protein in the spinal cord than endogenous mouse TDP-43. Expression is highest in the brain and spinal cord, with lower levels in other tissues.

The precise cause of death in the hybrid line is unknown; however, the congenic version was subsequently shown to die of bowel obstruction (Hatzipetros et al., 2013; Guo et al., 2012). The gut dysfunction and pathology is thought to result from transgene expression in the myenteric plexus.

Modification Details

In this model the transgene encodes full-length, human, mutant TARDBP with the A315T mutation and an N-terminal Flag tag. The mouse prion protein (PrP) promoter drives transgene expression.

Related Strains

TARDBP (A315T) (congenic) - This congenic model (C57BL/6J background) was derived from the original line and is available through The Jackson Lab, Stock# 010700 (B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J).

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

No Data

  • NMJ Abnormalities

Cortical Neuron Loss

By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.

Lower Motor Neuron Loss

By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.

Cytoplasmic Inclusions

By end-stage, cytoplasmic inclusions of ubiquitinated proteins in layer 5 neurons of motor, sensory, and cingulate cortex. Ubiquitin aggregates in ventral horn neurons. TDP-43 inclusions were rare.

Gliosis

By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.

NMJ Abnormalities

Unknown.

Muscle Atrophy

By end-stage, atrophic muscle fibers were observed.

Motor Impairment

Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.

Body Weight

Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.

Premature Death

Survival for about 5 months (154 ± 19 days) before dying spontaneously or being euthanized. It was not reported if this analysis includes males, females, or both.

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References

Research Models Citations

  1. TARDBP (A315T) (congenic)

Paper Citations

  1. . TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18809-14. Epub 2009 Oct 15 PubMed.
  2. . C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 2014 Oct 10;1584:59-72. Epub 2013 Oct 18 PubMed.
  3. . HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 2012 Jun 15;1460:88-95. PubMed.

External Citations

  1. The Jackson Lab, Stock# 010700

Further Reading