Research Models

TDP-43 (A315T) (line 23)

Species: Mouse
Genes: TARDBP
Mutations: TARDBP A315T
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: STOCK Tg(Prnp-TARDBP*A315T)23Jlel/J
Genetic Background: Transgene injected into fertilized hybrid B6SJLF1oocytes. Founders bred with CD1 to create hybrid CD1 and B6SJLF.
Availability: The Jackson Lab: Stock# 016143; Cryopreserved

Summary

This mouse model of ALS was among the first transgenics expressing mutant TDP-43 to be characterized (Stallings et al., 2010). In this model the mouse prion protein (Prp) promoter drives TDP-43 expression in the central nervous system, including in the brain and spinal cord, with lower expression elsewhere (i.e., skeletal muscle). Hemizygous mice develop progressive motor impairment, ultimately leading to paralysis and premature death at around 2.5 months of age.

The breeding strategy used to create TDP-43 (A315T) (line 23) produced several founders, many of which were born small and did not survive to reproduce. Intermediate levels of expression, such as the approximately fourfold overexpression in line 23, appear to be tolerated during development. 

Around one month of age, these mice first display symptoms of motor impairment, characterized by weakness, decline in grip strength, and reduction in stride length. Weakness was typically more pronounced in the hindlimbs at first, but ultimately progressed until the mice were unable to right themselves and were sacrificed. The mean survival was 75 days (Stallings et al., 2010). According to The Jackson Lab website in 2015, an increase in mean survival was seen in their colony. Median survival of hemizgous males and females was 109 and 164 days, respectively.

At end-stage, these mice do not show overt neuronal loss in the brain or spinal cord. However, neurons of the ventral horn and brainstem develop ubiquitin-positive cytoplasmic inclusions. TDP-43 aggregates in the cytoplasm are largely absent, although some rare inclusions were present at end-stage. Inclusions were typically accompanied by astrocytosis.

Muscle pathology was observed as well. Histological analysis of the quadriceps muscle showed atrophy of muscle fibers as well as angular fibers consistent with denervation of the muscle.

Prior to showing motor deficits, line 23 mice display metabolic abnormalities, including an increase in body fat, a decrease in lean muscle mass, larger adipocytes in white fat, and an impaired response to insulin. These phenotypes are attributed to TDP-43 overexpression in peripheral target organs (Stallings et al., 2013).

Modification Details

In this model the transgene encodes full-length, mutant, human TDP-43 with the A315T mutation. The mouse prion protein (Prp) promoter drives transgene expression.

Related Strains

TDP-43 (A315T) (hybrid) -This strain on a hybrid B6SJL background, is available through The Jackson Lab, Stock# 016203; Cryopreserved. B6SJL-Tg(Prnp-TARDBP*A315T)23Jlel/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

  • Cortical Neuron Loss
  • Lower Motor Neuron Loss

No Data

  • NMJ Abnormalities

Cortical Neuron Loss

Not observed.

Lower Motor Neuron Loss

Not observed.

Cytoplasmic Inclusions

Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Cytoplasmic aggregates of TDP-43 are largely absent, although rare phospho-TDP-43 inclusions were observed, especially at end-stage.

Gliosis

Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.

NMJ Abnormalities

Unknown.

Muscle Atrophy

Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.

Motor Impairment

Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.

Body Weight

Progressive weight loss.

Premature Death

Line 23 mice survived about 2.5 months, mean survival 75 days. It was not reported whether this survival analysis includes males, females or both. Colony at Jackson Labs has longer mean survival.

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References

Paper Citations

  1. . Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis. 2010 Nov;40(2):404-14. Epub 2010 Aug 2 PubMed.
  2. . TDP-43, an ALS Linked Protein, Regulates Fat Deposition and Glucose Homeostasis. PLoS One. 2013;8(8):e71793. PubMed.

External Citations

  1. The Jackson Lab, Stock# 016203
  2. The Jackson Lab: Stock# 016143

Further Reading