Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: C57BL/6-Tg(Prnp-TARDBP)3cPtrc/J
Genetic Background: Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6.
Availability: The Jackson Lab: Stock# 016608; Cryopreserved
This transgenic mouse model of ALS overexpresses wild-type human TDP-43. Hemizygous mice are largely indistinguishable from non-Tg mice; however, homozygous mice develop severe motor impairments requiring euthanasia between one and two months of age (Xu et al., 2010).
In this model, the mouse prion protein (Prp) promoter drives transgene expression, resulting in robust expression in the brain and spinal cord and lower levels in other tissues. In the brain, human TDP-43 protein was 1.9-fold higher than endogenous TDP-43 in hemizygotes, and 2.5-fold higher in homozygotes. Human TDP-43 was primarily nuclear, but occasional cytoplasmic protein was also seen in some CNS neurons. Endogenous murine TDP-43 was downregulated in the presence of exogenous human TDP-43 (see also Xu et al., 2013).
The earliest reported phenotypic difference between homozygous TDP-43 (Prp) mice and non-Tg controls is a divergence in body weight, starting at postnatal day 14. By day 21 homozygous mice develop body tremors and reduced walking speed, followed by gait difficulties, described as a “swimming gait,” because the mice are unable to hold their bodies off the ground. By one to two months of age, they are unable to right themselves and require euthanasia.
The underlying cause of the motor deficit is not clear. The mice do not appear to be affected by muscle atrophy or loss of motor neurons. However, signs of neuronal degeneration are present in the form of degenerating neurites and axons in the brain and spinal cord. Synaptic pathology has also been observed, specifically fewer dendritic spines in the hippocampus and lower mRNA levels or synaptic markers including PSD-95 and GAP43 (Xu et al., 2013).
Neuroinflammation is a prominent feature involving activated microglia and reactive astrocytes. Distinct mitochondria pathology is observed within neurons, specifically electron microscopy showed abnormal clusters of mitochondria, suggestive of defective fission/fusion. Aggregates of cytoplasmic TDP-43 are notably absent, but elevated levels of ubiquitin are seen within the nucleus and cytoplasm of neurons in the brain and spinal cord.
These mice overexpress wild-type human TARDBP driven by the mouse prion protein (Prp) promoter.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cortical Neuron Loss
- Lower Motor Neuron Loss
- Muscle Atrophy
- NMJ Abnormalities
Cortical Neuron Loss
Lower Motor Neuron Loss
Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.
Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.
Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.
Atrophy of the gastrocnemius muscle was not observed.
By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.
Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.
Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.
- Xu YF, Gendron TF, Zhang YJ, Lin WL, D'Alton S, Sheng H, Casey MC, Tong J, Knight J, Yu X, Rademakers R, Boylan K, Hutton M, McGowan E, Dickson DW, Lewis J, Petrucelli L. Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci. 2010 Aug 11;30(32):10851-9. PubMed.
- Xu YF, Prudencio M, Hubbard JM, Tong J, Whitelaw EC, Jansen-West K, Stetler C, Cao X, Song J, Zhang YJ. The Pathological Phenotypes of Human TDP-43 Transgenic Mouse Models Are Independent of Downregulation of Mouse Tdp-43. PLoS One. 2013;8(7):e69864. PubMed.