Mutations: TARDBP G348C
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 backcrossed with C57Bl/6.
Availability: Available through Jean-Pierre Julien
These transgenic mice develop neuropathology and behavioral deficits relevant to ALS and FTD, including cytoplasmic inclusions of TDP-43 protein, axonal pathology, neuroinflammation, learning/memory deficits, and motor impairment. They do not develop overt neuronal or axonal loss, nor do they develop paralysis (Swarup et al., 2011).
Compared to many other TDP-43 transgenics, these mice express relatively modest levels of human TDP-43, relying on the endogenous human TDP-43 promoter to drive expression. In the brain, transgene mRNA expression was about threefold higher than endogenous murine TDP-43 mRNA. Protein levels of human TDP-43 were highest in the brain, spinal cord, and muscle, with lower levels in the liver and kidney, mimicking endogenous expression patterns.
Despite modest overexpression, these mice develop quite robust TDP-43 pathology, including an accumulation of cytoplasmic TDP-43 in motor neurons in the spinal cord by 10 months of age. Some of this cytoplasmic TDP-43 was in the form of aggregates, which often co-localized with ubiquitin. Elevated levels of the 25 kDA fragment of TDP-43 were found in the brain and spinal cord.
Abnormalities in various cytoskeletal proteins were observed, including aggregates of the intermediate filament protein, peripherin, in the brain and spinal cord at 10 months of age. Neurofilament proteins (both heavy and light chain) were downregulated in the spinal cord at 10 months of age, compared with non-Tg mice.
Overt neuronal loss is not seen in these mice, nor is axonal loss. However, abnormalities of the neuromuscular junction were observed in 10-month-old TDP-43 G348C mice. About 10 percent of the NMJs were fully denervated, and another 20 percent were partially denervated. In the spinal cord, differences in the caliber of axons at the L5 ventral root were also observed.
Neuroinflammation was detectable early, by three months of age, and prior to the onset of behavioral abnormalities. Astrogliosis and microgliosis started early in the brain and spinal cord and continued to progress with age.
Behaviorally, these mice displayed both cognitive and motor deficits. Deficits were seen at seven months of age in the passive-avoidance test, a measure of contextual learning. Likewise, deficits in spatial learning were observed in the Barnes maze by 10 months of age. The mice also exhibited progressive impairment on the Rotarod starting at 36 weeks of age.
Compared with non-Tg mice, TDP-43 G348C transgenics had impaired recovery from nerve injury (Swarup et al., 2012). Recovery from crush injury to the sciatic nerve was slow and incomplete in three-month-old TDP-43 mice. Eleven days after injury, the mice had elevated neuroinflammation and fewer regenerating axons.
Data on this page refer to hemizygous mice.
These mice overexpress full-length human TDP-43 with the G348C mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human promoter.
Available through Jean-Pierre Julien.
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
- Premature Death
- Muscle Atrophy
- Body Weight
Cortical Neuron Loss
Lower Motor Neuron Loss
Cytoplasmic accumulation of TDP-43 was observed by 10 months in the spinal cord. Cytoplasmic aggregates occurred and often co-localized with ubiquitin. These inclusions are not detected at 3 months of age.
Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.
In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.
Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.
Research Models Citations
- Swarup V, Phaneuf D, Bareil C, Robertson J, Rouleau GA, Kriz J, Julien JP. 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.
- Swarup V, Audet JN, Phaneuf D, Kriz J, Julien JP. 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.
No Available Further Reading