Research Models
Find A Model By Name
Search Research Models
Search Results
20 Models
20 Visualizations
ALS-related Research Models
- Sex-specific differences
- Cortical Neuron Loss
- Lower Motor Neuron Loss
- Cytoplasmic Inclusions
- Gliosis
- NMJ Abnormalities
- Muscle Atrophy
- Motor Impairment
- Body Weight
- Premature Death
hTDP-43ΔNLS
Observed
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.
Absent
Not observed.
Absent
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).
Observed
Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.
No Data
Unknown.
Absent
Not observed.
Observed
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.
No Data
Unknown.
Absent
Not observed.
NEFH-tTA x hTDP-43ΔNLS
Observed
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.
Observed
rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.
Observed
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.
Observed
Astrogliosis develops in many brain regions, including layer V of the motor cortex.
Observed
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.
Observed
At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.
Observed
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).
Observed
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.
Observed
rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.
TARDBP (A315T) (congenic)
No Data
These mice lose corticospinal tract axons, but outright loss of cortical neurons has not been reported in the model. When crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, mice expressing TDP-43 (A315T) had fewer neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016).
Absent
Most studies reported no lower motor neuron loss. One study observed 20% loss of large ventral horn neurons, possibly dependent on diet and how long the mice live in an individual colony.
Observed
Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.
Observed
Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.
Observed
Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).
Observed
Atrophy of gastrocnemius muscle (gel diet).
Observed
Deficits have been reported in nonspecific measures of strength and coordination such as the Rotarod (males and females) and hanging-wire test (males). A severely impaired gait (“swimming gait”) was observed in mice fed a gel diet.
Observed
Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.
Observed
Survival is limited by severe gastrointestinal dysfunction and can be prolonged with a gel diet. Lifespan varies, but in general on a standard diet males live about 3 months and females about 6 months.
TARDBP (A315T) (hybrid)
Observed
By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.
Observed
By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.
Observed
By end-stage, cytoplasmic inclusions of ubiquitinated proteins in layer 5 neurons of motor, sensory, and cingulate cortex. Ubiquitin aggregates in ventral horn neurons. TDP-43 inclusions were rare.
Observed
By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.
No Data
Unknown.
Observed
By end-stage, atrophic muscle fibers were observed.
Observed
Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.
Observed
Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.
Observed
Survival for about 5 months (154 ± 19 days) before dying spontaneously or being euthanized. It was not reported if this analysis includes males, females, or both.
Tardbp Q331K Knock-In
No Data
No data.
No Data
No data.
No Data
No data.
No Data
No data.
No Data
No data.
No Data
No data.
No Data
No data.
No Data
No data.
No Data
No data.
Tardp LCDmut
No Data
No data.
Observed
28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with non-transgenic littermates.
Observed
At 18 months of age, p62- and ubiquitin-positive inclusions are found in the ventral regions of the spinal cord, although these inclusions do not appear to be located in the cytoplasm of motor neurons.
No Data
No data.
Observed
By 24 months, a 15 percent reduction in motor units innervating the extensor digitorum muscle.
No Data
No data.
Observed
Grip strength in both male and female mice begins to decline at 12 months of age. By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles.
No Data
No data.
Absent
Do not exhibit premature death, at least until 24 months of age.
Tardp_RRM2mut
No Data
No data.
Absent
Not observed at 2 years.
Absent
Not observed at 2 years.
No Data
No data.
Absent
Not observed at 2 years.
No Data
No data.
Absent
Not observed at 2 years.
No Data
No data.
Absent
Homozygous mutation is embryonic lethal.
TDP-43 (A315T)
Absent
Not observed.
Absent
Not observed.
Observed
Cytoplasmic accumulation of TDP-43 was observed by 10 months of age in the spinal cord. Furthermore, cytoplasmic aggregates were observed and often co-localized with ubiquitin. These inclusions are not detected at three months of age.
Observed
Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.
No Data
Unknown.
No Data
Unknown.
Observed
At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.
No Data
Unknown.
Absent
Not observed.
TDP-43 (A315T) (line 23)
Absent
Not observed.
Absent
Not observed.
Observed
Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Cytoplasmic aggregates of TDP-43 are largely absent, although rare phospho-TDP-43 inclusions were observed, especially at end-stage.
Observed
Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.
No Data
Unknown.
Observed
Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.
Observed
Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.
Observed
Progressive weight loss.
Observed
Line 23 mice survived about 2.5 months, mean survival 75 days. It was not reported whether this survival analysis includes males, females or both. Colony at Jackson Labs has longer mean survival.
TDP-43 (G348C)
Absent
Not observed.
Absent
Not observed.
Observed
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.
Observed
Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.
Observed
In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.
No Data
Unknown.
Observed
Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.
No Data
Unknown.
Absent
Normal lifespan.
TDP-43 (M337V)
Absent
Not observed.
Absent
Not observed.
Observed
TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.
Observed
Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.
No Data
No data.
No Data
No data.
Observed
Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”
Observed
By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.
Observed
70% mortality of homozygotes by around one month of age.
TDP-43 (M337V) (Mt-TAR6/6)
Observed
Severe neuronal loss in all CA regions of the hippocampus of homozygous mice. Neuronal loss was also observed in layer V cortical neurons and thalamic neurons.
Observed
Neuronal loss was observed in the spinal cords of homozygous mice.
Observed
Some homozygous mice developed cytoplasmic inclusions in layer V cortical neurons. These were often, but not always, ubiquitin–positive. They were not universally observed, even in end-stage mice.
Observed
Elevated astrogliosis and microgliosis compared with non-Tg controls, especially in the motor cortex and spinal cord. Gliosis in the hippocampus was seen at end stage.
No Data
Unknown.
No Data
Unknown.
Observed
Motor impairment developed quickly, by 11 days of age in homozygous mice, starting with an abnormal clasping reflex. They also develop a hunched posture, muscle twitches, and reduced mobility. Paralysis developed within days, leading to death. Hemizygotes do not develop motor symptoms until about one year of age, and impairment varied from mouse to mouse.
Observed
Early postnatal growth retardation in homozygous mice. By day 17 their average body weight is about half that of non-Tg controls.
Observed
Homozygous mice survived an average of just 17 days. In contrast, hemizygous Mt-TAR6 mice lived up to 24 months (average survival ~16.4 months).
TDP-43 (Q331K)
No Data
Unknown.
Observed
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.
Absent
TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.
Observed
Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.
Observed
Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.
No Data
Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.
Observed
Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.
No Data
Unknown.
No Data
Unknown.
TDP-43 (Q331K) Knock-In (Line 52)
Observed
25% loss of parvalbumin-positive neurons at 5 months.
Absent
Not observed.
Absent
Not observed.
No Data
Unknown.
Absent
Not observed.
No Data
Unknown.
Absent
Not observed.
Observed
Increased body weight.
Observed
Mutation may be deleterious to male embryos.
TDP-43 (WT) (Elliott)
Absent
Not observed.
Absent
Not observed.
Observed
Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.
No Data
No data.
No Data
No data.
Observed
An analysis of the quadriceps muscle, showed signs of myopathy, including variable muscle fiber size and disorganization of the muscle architecture.
Observed
Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.
Observed
Progressive weight loss.
Observed
The mean survival of hemizygous mice was 109 days (it is not clear if this value represents males, females, or both).
TDP-43 (WT) (Julien model)
Absent
Not observed.
Absent
Not observed.
Absent
Primarily nuclear localization of human TDP-43.
Observed
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.
Observed
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.
No Data
No data.
Observed
Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.
No Data
No data.
No Data
No data.
TDP-43 (WT) (Kumar-Singh)
Observed
In homozygous mice, quantitative loss of neurons occurs in the motor cortex compared with non-Tg littermates. Both superficial and deep cortical layers of the anterior cortex are affected.
Observed
By day 18, homozygous mice exhibited about 25 percent loss of motor neurons in the lumbar spinal cord compared with non-Tg littermates.
Observed
Homozygous mice developed cytoplasmic inclusions in the brain and spinal cord, many of which were ubiquitin-positive. A minority of inclusions co-labeled with TDP-43. Ultrastructural analysis revealed ubiquitin–negative cytoplasmic inclusions in anterior horn neurons to be abnormal accumulations of mitochondria.
Observed
Astrogliosis and microgliois especially in cortical layer V of the anterior cortex, including motor and somatosensory cortex, and in the spinal cord.
No Data
No data.
No Data
No data.
Observed
Homozygous mice exhibit an abnormal clasping reflex by postnatal day 14. Other early motor deficits include a shortened stride, a wide stance, and frequent stumbling. By day 18, reduced performance on the Rotarod. Complete paralysis occurs ~10 days after onset.
Observed
Size and weight of homozygous mice lag behind hemizygotes and non-Tg littermates.
Observed
Homozygous mice survive an average of just 24 days. In contrast, hemizygous mice survive to advanced age, although they die more prematurely than non-Tg mice, after 22 to 24 months.
TDP-43 (WT) (Petrucelli)
Absent
Not observed.
Absent
Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.
Observed
Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.
Observed
Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.
No Data
Unknown.
Absent
Atrophy of the gastrocnemius muscle was not observed.
Observed
By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.
Observed
Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.
Observed
Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.
TDP-43 (Wt-TAR6/6)
Observed
Approximate 15 percent loss of layer V neurons in motor cortex at 6 months.
Observed
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.
Observed
Inclusions containing phosphorylated TDP-43 rarely observed in the nuclei and cytoplasm of spinal neurons.
Observed
Microgliosis in cortex and spinal cord prominent at 6 months; astrogliosis in cortex and spinal cord apparent at 1.5 months.
No Data
No data.
Observed
Muscle wasting, particularly in flanks.
Observed
Progressive motor impairment; abnormal hind limb reflexes observed as early as 1.5 months.
Observed
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).
Observed
Average survival is 6.7 months.
ΔNLS-FUS x TDP-43(WT)
Observed
By 1 year, there was neuronal loss in the motor cortex.
Absent
Not observed at 1 year in the L5 anterior horn.
Observed
Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.
Observed
Microgliosis and astrocytosis were observed in the motor cortex.
No Data
No data.
No Data
No data.
Observed
Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire test.
Observed
Decreased by 48 weeks.
Observed
Approximately 40% mortality by 60 weeks of age.