Mutations: TARDBP Q331K
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: Transgene introduced into C57Bl6/C3H oocytes. Founders crossed to C57/Bl6 for a minimum of four generations.
This transgenic mouse model of ALS overexpresses human TDP-43 with the Q331K mutation (Arnold et al., 2013). Expression of the mutant protein is driven in the brain and spinal cord by the mouse prion protein (Prp) promoter. Although this model does not recapitulate cytoplasmic mislocalization of TDP-43, it does develop age-dependent motor deficits, degeneration of lower motor neurons, and abnormalities at the neuromuscular junction.
The line focused on here, line 103, was generated in parallel with two other lines expressing TDP-43 with the Q331K mutation (line 109 and line 31). Line 103 is the best characterized of the three and had the greatest transgene expression (about threefold more total TDP-43 RNA in the spinal cord compared with non-Tg mice). Consistent with TDP-43 autoregulation, a decrease in endogenous murine levels was observed in transgenic mice. Transgene expression was highest in the brain and spinal cord with very low levels observed in other tissues.
At birth, the TDP-43 Q331K mice were indistinguishable from non-Tg littermates. Tremor was observed as early as three to four months of age in some mice, and about 80 percent of animals were affected by 10 months of age. Abnormal hindlimb clasping affected about 60 percent of animals by three months of age. Performance on the accelerating Rotarod was normal at 21 days of age, but impaired by three months. Grip strength was affected later, by about 10 months of age.
The motor impairments were accompanied by muscle pathology, including abnormal electromyographic (EMG) activity in the gastrocnemius muscle. Resting EMG recordings showed muscle fibrillations, suggesting neuromuscular degeneration. H&E staining showed muscle fiber abnormalities, including centralized nuclei. At 10 to 12 months the mice had fewer neuromuscular junctions (NMJs) as quantified by α-bungarotoxin staining. Furthermore, NMJs were described as malformed, with a “bleb-like” appearance.
Age-dependent neurodegeneration of lower motor neurons occurred in the spinal cord. Specifically, reduced numbers of choline acetyl-transferase (ChAT)–positive neurons were seen in the lumbar spinal cord. Neuronal loss was detected as early as two months of age, with an overall 35 percent reduction at 10 months of age compared with non-Tg mice or those expressing comparable levels of wild-type TDP-43. In addition, astrogliosis and microgliosis developed in the ventral horn of the spinal cord by 10 to 12 months of age.
The majority of human TDP-43 was present in the nuclear fraction of brain and spinal cord homogenate of 10- to 20-month-old mice. Immunohistochemistry of the spinal cord confirmed predominantly nuclear localization of TDP-43.
This transgenic model expresses full-length human TDP-43 with the Q331K mutation driven by the mouse prion protein (Prp) promoter.
Two other TDP-43 transgenic models were reported in parallel: TDP-43 (wild-type) and TDP-43 (M337V) (Arnold et al., 2013).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cytoplasmic Inclusions
- Cortical Neuron Loss
- Muscle Atrophy
- Body Weight
- Premature Death
Cortical Neuron Loss
Lower Motor Neuron Loss
Age-dependent loss of lower motor neurons in the lumbar spinal cord. Loss is detectable as early as 2 months of age and is more pronounced by 10 months.
TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.
Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.
Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.
Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.
Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.
- Arnold ES, Ling SC, Huelga SC, Lagier-Tourenne C, Polymenidou M, Ditsworth D, Kordasiewicz HB, McAlonis-Downes M, Platoshyn O, Parone PA, Da Cruz S, Clutario KM, Swing D, Tessarollo L, Marsala M, Shaw CE, Yeo GW, Cleveland DW. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):E736-45. PubMed.
No Available Further Reading