Species: Mouse
Genes: TARDBP
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Summary
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.
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
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.
Cytoplasmic Inclusions
TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.
Gliosis
Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.
NMJ Abnormalities
Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.
Muscle Atrophy
Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.
Motor Impairment
Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: TARDBP
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: B6;C3-Tg(NEFH-tTA)8Vle Tg(tetO-TARDBP*)4Vle/J
Summary
Phenotype Characterization
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
Decreased cortical thickness indicative of neuronal degeneration beginning at four weeks off dox. By end stage, rNLS8 mice had significantly smaller brains than non-Tg littermates.
Lower Motor Neuron Loss
rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.
Cytoplasmic Inclusions
Cytoplasmic inclusions of TDP-43 occur as early as one week off dox in neurons in the brain. Inclusions accumulate over time and are present in many brain regions, including the motor cortex. TDP-43 inclusions are relatively rare in the spinal cord. Ubiquitin-positive inclusions are also seen.
Gliosis
Astrogliosis develops in many brain regions, including layer V of the motor cortex.
NMJ Abnormalities
Denervation of the hindlimb muscle tibialis anterior was detectable by four weeks off dox, that is, two weeks prior to detectable loss of lower motor neurons.
Muscle Atrophy
At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.
Motor Impairment
rNLS8 mice develop a variety of motor impairments, starting with a deficit in hindlimb clasping and a fine tremor in the forelimb and/or hindlimb. They also develop progressive loss of grip strength (as measured by the wire-hang test) and a progressive decline in coordinated movement and balance (as measured by the accelerating Rotarod).
Body Weight
Body mass peaked at approximately 7 weeks of age (i.e., two weeks off dox) and then progressively dropped. Excessive loss of body weight (>30% decrease from peak weight) often defined end-stage.
Premature Death
rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.
Last Updated: 14 Jun 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: TARDBP
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Summary
These transgenic mice, which are now extinct, overexpressed wild-type human TDP-43. They developed motor and cognitive deficits relevant to ALS/FTD, along with pertinent neuropathology, including gliosis and denervation of neuromuscular junctions. Phenotypes were generally milder than what had been observed in mice overexpressing mutant TDP-43 (e.g., TDP-43 A315T and TDP-43 G348C) (Swarup et al., 2011).
Phenotype Characterization
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
Primarily nuclear localization of human TDP-43.
Gliosis
Gliosis, both microgliosis and astrogliosis, occur early in the brain and spinal cord. Reactive glia were detected as early as 3 months of age, with more by 10 months.
NMJ Abnormalities
Some NMJ denervation was observed by 10 months of age. About 5% of NMJs at the gastrocnemius muscle were denervated, with another 20 percent partially denervated.
Motor Impairment
Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.
Last Updated: 05 Jun 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: TARDBP
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: B6;C3-Tg(tetO-TARDBP*)4Vle/J
Summay
Under physiological conditions TDP-43 is primarily nuclear, but in some people with ALS and FTD the protein relocates to the cytoplasm where it accumulates into hallmark inclusions. To investigate the consequences of TDP-43 mislocalization, this mouse model overexpresses TDP-43 targeted to the cytoplasm through removal of the nuclear localization signal (NLS) from the transgene (Igaz et al., 2011).
Phenotype Characterization
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
Severe neuronal degeneration in the dentate gyrus and deep layers of the neocortex. Other regions, such as the hippocampal CA1 subfield and olfactory bulb, were relatively resistant to neurodegeneration. Approximately 50 percent of dentate gyrus neurons were lost one month after the transgene was activated.
Cytoplasmic Inclusions
High levels of cytosolic TDP-43 but only very rare aggregates (observed in less than 1 percent of cortical neurons and even rarer in other brain regions, such as the hippocampus and striatum).
Gliosis
Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.
Motor Impairment
Spastic motor impairment indicated by an abnormal clasping response as early as one week after transgene induction. A variety of motor deficits develop by one month after transgene induction, including impaired coordination on the Rotarod and decreased grip strength.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: TARDBP
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: C57BL/6-Tg(Prnp-TARDBP)3cPtrc/J
Summary
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).
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
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 Inclusions
Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.
Gliosis
Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.
Muscle Atrophy
Atrophy of the gastrocnemius muscle was not observed.
Motor Impairment
By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.
Body Weight
Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.
Premature Death
Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.
Last Updated: 13 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: TARDBP
Mutations: TARDBP M337V
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: C57BL/6-Tg(Prnp-TARDBP*M337V)4Ptrc/J
Summary
Phenotype Characterization
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
TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.
Gliosis
Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.
Motor Impairment
Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”
Body Weight
By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.
Premature Death
70% mortality of homozygotes by around one month of age.
Last Updated: 05 Jun 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: TARDBP
Mutations: TARDBP G348C
Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Summary
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).
Phenotype Characterization
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
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.
Gliosis
Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.
NMJ Abnormalities
In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.
Motor Impairment
Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: C9orf72
Mutations: Hexanucleotide repeat in C9ORF72
Modification: C9orf72: Virus
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Summary
Phenotype Characterization
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
Compared with mice expressing 2-repeats, the 66-repeat mice had 17 percent fewer neurons in the cortex at 6 months of age and 11 percent fewer Purkinje cells in the cerebellum. At this age neurons in the hippocampus and thalamus were not affected.
Lower Motor Neuron Loss
At 6 months, neuronal loss in the spinal cord was not detected.
Cytoplasmic Inclusions
By 6 months, inclusions of C9RAN dipeptides were present in neurons of the cortex and hippocampus, and to a lesser extent in the cerebellum and spinal cord. Inclusions contained polyGA, polyGP, and polyGR dipeptides and were largely ubiquitin-positive.
Gliosis
Astrogliosis in the cortex by 6 months.
Motor Impairment
At 6 months, 66-repeat mice perform as well as 2-repeat mice on the Rotarod on the first day of testing. However, they fail to improve during subsequent trials, suggesting impairments in coordination and/or motor learning.
Body Weight
At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.
Last Updated: 11 Dec 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: C9orf72
Mutations: Hexanucleotide repeat in C9ORF72
Modification: C9orf72: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: N/A
Summary
Phenotype Characterization
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
No cytoplasmic mislocalization, or aggregation of TDP-43 in the motor cortex. However, dipeptide repeats accumulated at advanced age and formed small perinuclear inclusion bodies positive for poly-GP.
Gliosis
No signs of increased activation of microglia or astrocytes in the brain or spinal cord.
NMJ Abnormalities
No difference in denervation of neuromuscular junctions at 24 months of age. No difference in motor or sensory spinal nerve root axon number or morphology.
Muscle Atrophy
Muscle histology has not been reported, but no overt muscle atrophy was observed.
Motor Impairment
No overt motor deficit as measured by the Rotarod and grip strength.
Body Weight
Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.
Premature Death
Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.
Last Updated: 04 Jun 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: FUS
Mutations: FUS R521C
Modification: FUS: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: B6;SJL-Tg(Prnp-FUS*R521C)3313Ejh/J
Summary
At a young age, this transgenic mouse develops severe motor impairment and other ALS-related phenotypes. Notably, it develops robust neuronal loss in the spinal cord, denervation of neuromuscular junctions, and muscle atrophy. Phenotype development is swift—detectable within weeks of birth—and the mice decline rapidly. Most mice in the original N1F1 generation reached end-stage within three months (Qiu et al., 2014).
Phenotype Characterization
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
No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.
Lower Motor Neuron Loss
No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.
Cytoplasmic Inclusions
Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.
Gliosis
Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.
NMJ Abnormalities
Reduced innervation of neuromuscular junctions in the diaphragm.
Muscle Atrophy
The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.
Motor Impairment
Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.
Body Weight
Early postnatal growth is retarded, and the mice experience progressive loss of body weight.
Premature Death
The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.
Last Updated: 30 Nov 2018
Further Reading
No Available Further Reading
Subhojit Roy 
Caroline Vance 
COMMENTS / QUESTIONS
No Available Comments
Make a comment or submit a question
To make a comment you must login or register.