Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J.
Availability: The CRO QPS-Austria offers research with TAR6/6 mice.
This mouse model of ALS expresses wild-type human TDP-43 in postnatal neurons. Mice homozygous for the human TARDP transgene are referred to as TAR6/6, while mice hemizygous for the transgene are called TAR6. This description refers to homozygous, TAR6/6, mice. These mice exhibit neuropathological features of ALS, including elevated amounts of cytoplasmic and insoluble TDP-43, astrogliosis and microgliosis, and loss of motor neurons in the cortex and spinal cord; motor impairment; and early death.
Transgenic human TDP-43 is expressed in the brains and spinal cords of TAR6/6 mice at levels similar to the endogenous mouse protein (Wils et al., 2010; Scherz et al., 2018). Although TDP-43 levels in the brains of TAR6/6 mice remain stable with age, levels in spinal cord decline between 1.5 and 6 months, paralleling a decrease in mouse TDP-43 observed in non-transgenic animals (Scherz et al., 2018). In addition to full-length TDP-43, a 35-kDa C-terminally truncated fragment (CTF-35) is generated, with a fivefold increase in homogenates from whole brains of TAR6/6 mice compared with non-transgenic mice, and 20- and 10- fold increases in hippocampi and spinal cords, respectively (Scherz et al., 2018).
Similar to non-transgenic mice, most TDP-43 is located in the nuclei of neurons in 3-month-old TAR6/6 mice. However, CTF-35 and human TDP-43 also accumulate in the cytoplasm (Wils et al., 2010; Scherz et al., 2018). Detergent-insoluble TDP-43 is also enriched in the brains of TAR6/6 mice, compared with non-transgenic animals. Inclusions containing phosphorylated TDP-43 are present in the nuclei and cytoplasm of only 2 percent of spinal neurons in TAR6/6 mice (Wils et al., 2010).
Motor neuron loss is detected in the spinal cord as early as 3 months of age (Scherz et al., 2018), and by 6 months, the number of anterior horn neurons in lumbosacral regions is reduced by approximately 10 percent (Wils et al., 2010). Upper motor neuron loss also occurs, with approximately 15 percent fewer neurons in layer V of the motor cortices of 6-month-old TAR6/6 mice, compared with non-transgenic animals (Wils et al., 2010).
Microgliosis in the cortex (Wils et al., 2010; Scherz et al., 2018) and spinal cord (Wils et al., 2010) is prominent at 6 months. Astrogliosis has also been reported (Wils et al., 2010; Scherz et al., 2018), although the time course of this response varied with the method used for characterization—appearing by 1.5 months and resolving by 6 months when assessed as the area of GFAP immunoreactivity (Scherz et al., 2018), but persisting at 6 months when assessed as the number of GFAP-immunoreactive cells (Wils et al., 2010).
TAR6/6 mice display progressive motor impairments. Abnormal hind limb reflexes and reduced muscle strength were observed as early as 6 weeks of age (Scherz et al., 2018). By 2 months of age, mice exhibit poor grooming, reduced spontaneous movement, and the onset of a progressive symmetrical paralysis of the hind limbs (Wils et al., 2010). Deficits in the Rotarod were not observed until 3.5 months of age (Scherz et al., 2018). In addition to motor impairment, TAR6/6 mice also show reduced anxiety and disturbed nesting behavior (Scherz et al., 2018).
Animals experience early death. Average survival is 6.7 months (Wils et al., 2010), with approximately 50 percent mortality at 20 weeks (QPS in-house observations).
Transgene encodes wild-type human TARDBP, driven by the murine Thy-1.2 promoter.
WT-TAR4/4. These mice were generated in parallel with the TAR6/6 line and carry the same genetic construct (Wils et al., 2010). TAR4/4 mice express higher levels of wild-type transgenic TDP-43 protein (approximately 1.7 times the amount of the TAR6/6 line), and have a more severe phenotype. Abnormal hind limb reflexes, retarded growth, and weight loss are already apparent at 2 weeks; complete paralysis and death occur by 4 weeks.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- NMJ Abnormalities
Cortical Neuron Loss
Approximate 15 percent loss of layer V neurons in motor cortex at 6 months.
Lower Motor Neuron Loss
Spinal motor neuron loss observed at 3 months, with approximately 10 percent fewer anterior horn neurons in lumbosacral regions at 6 months, compared with non-transgenic mice.
Inclusions containing phosphorylated TDP-43 rarely observed in the nuclei and cytoplasm of spinal neurons.
Microgliosis in cortex and spinal cord prominent at 6 months; astrogliosis in cortex and spinal cord apparent at 1.5 months.
Muscle wasting, particularly in flanks.
Progressive motor impairment; abnormal hind limb reflexes observed as early as 1.5 months.
TAR6/6 mice had lower body weights than non-transgenic mice between 3.25 and 3.75 months age, but the two genotypes were similar at younger and older ages (at least until 4.25 months).
Average survival is 6.7 months.
Last Updated: 21 Sep 2018
Research Models Citations
- Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3858-63. Epub 2010 Feb 3 PubMed.
- Scherz B, Rabl R, Flunkert S, Rohler S, Neddens J, Taub N, Temmel M, Panzenboeck U, Niederkofler V, Zimmermann R, Hutter-Paier B. mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms. PLoS One. 2018;13(5):e0197674. Epub 2018 May 22 PubMed.
- Janssens J, Wils H, Kleinberger G, Joris G, Cuijt I, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S. Overexpression of ALS-associated p.M337V human TDP-43 in mice worsens disease features compared to wild-type human TDP-43 mice. Mol Neurobiol. 2013 Aug;48(1):22-35. Epub 2013 Mar 10 PubMed.