Mutations: TARDBP M337V
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: C57BL/6-Tg(Prnp-TARDBP*M337V)4Ptrc/J
Genetic Background: Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6.
Availability: The Jackson Lab: Stock# 017604; Cryopreserved
This transgenic mouse model of ALS overexpresses mutant human TDP-43. It was generated by Leonard Petrucelli and colleagues at the Mayo Clinic (Xu et al., 2011). Like the wild-type TDP-43 transgenics reported by the Mayo group one year earlier (Xu et al., 2010), this model uses the mouse prion protein (Prp) promoter to drive transgene expression. Hemizygous mice are indistinguishable from non-Tg littermates, but homozygotes develop TDP-43 pathology, neuroinflammation, and severe motor impairment precipitating euthanasia at one to two months of age.
In homozygous TDP-43M337V mice, levels of mutant human TDP-43 are highest in the brain and spinal cord with lower levels in other tissues. Total TDP-43 (human and mouse) is elevated about 2.7-fold over levels in non-Tg littermates. This is likely an under-representation of transgene expression because mouse TDP-43 is downregulated in the presence of exogenous human TDP-43 (see also Xu et al., 2013). TDP-43 protein was primarily nuclear, however, some cytoplasmic TDP-43 was observed in neurons of the spinal cord, brainstem, and cortex. Phosphorylated TDP-43 (at serine 403 and 404) was frequently seen in motor neurons of the anterior horn of the spinal cord, among other areas. Likewise, widespread ubiquitination was observed in CNS neurons, but TDP-43 itself did not appear to be ubiquitinated. Hyperphosphorylated tau protein also accumulated in the brain, with extensive staining throughout the neuropil and some cytoplasmic inclusions within neurons.
Mitochondrial abnormalities were also seen in these mice, appearing as cytoplasmic eosinophilic aggregates in neurons. These aggregates were frequent in the anterior horn of the spinal cord and brainstem, but also appeared in other areas. Neuroinflammation was prominent, appearing as elevated levels of reactive astrocytes and activated microglia in the spinal cord and brainstem.
Motor impairment developed early in TDP-43M337V homozygotes. By day 21 they developed tremors and difficulty recruiting their hindlimbs. This impairment led in an irregular gait pattern, described as “dragging.” By one month of age, 70 percent of homozygotes had lost the ability to right themselves, were moribund, and required euthanasia. Not surprisingly, survivors at one month of age had reduced brain and body weight compared with non-Tg littermates.
Despite the severe motor impairment exhibited by these mice, neuronal loss was not observed in the brain or spinal cord.
These mice overexpress full-length human TARDBP with the M337V mutation. The transgene is 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
- NMJ Abnormalities
- Muscle Atrophy
Cortical Neuron Loss
Lower Motor Neuron Loss
TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.
Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.
Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”
By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.
70% mortality of homozygotes by around one month of age.
- Xu YF, Zhang YJ, Lin WL, Cao X, Stetler C, Dickson DW, Lewis J, Petrucelli L. Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Mol Neurodegener. 2011 Oct 26;6:73. PubMed.
- 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.