Research Models
ALS Mouse Models
Dozens of rodents have been generated that model various aspects of ALS, like motor impairment or degeneration of motor neurons. No model recapitulates the human disease perfectly. By organizing information related to the phenotypic characterization of selected ALS models, this resource conveys what is known about each one and facilitates comparison between models. The curation of ALS models was supported in part by a grant from the NINDS.
- Sex-specific differences
- Cortical Neuron Loss
- Lower Motor Neuron Loss
- Cytoplasmic Inclusions
- Gliosis
- NMJ Abnormalities
- Muscle Atrophy
- Motor Impairment
- Body Weight
- Premature Death
AAV-GFP-(GA)50
Observed
At 6 months, neuron loss observed in cortex, including layer V of motor cortex.
No Data
No data.
Observed
Neuronal poly(GA)- and ubiquitin-positive inclusions already present at 4-6 weeks; rare TDP-43-positive inclusions.
Observed
Astrogliosis, but not microgliosis, in cortex and hippocampus, seen at 6 months.
No Data
No data.
No Data
No data.
Observed
Deficits in tail-suspension and rotarod tests, seen at 6 months.
Observed
Decreased body weight in males, but not females, seen at 6 months.
No Data
No data.
AAV-GFP–(GR)100
Observed
Fewer cortical neurons than controls, observed as early as 6 weeks of age.
Absent
Not observed up to 6 months of age.
Observed
Very rare TDP-43 inclusions, observed at 6 months.
Observed
Astrogliosis and microgliosis in cortex and hippocampus, observed at 6 weeks.
No Data
No data.
No Data
No data.
Observed
Progressive motor deficits, seen in open-field, rotarod, rod-walk, and wire-hang tests.
Absent
Normal at 6 months of age.
No Data
No data.
C9-BAC500 (Brown)
Absent
Not observed.
Absent
Not observed.
Observed
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.
Absent
No signs of increased activation of microglia or astrocytes in the brain or spinal cord.
Absent
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.
No Data
Muscle histology has not been reported, but no overt muscle atrophy was observed.
Absent
No overt motor deficit as measured by the Rotarod and grip strength.
Absent
Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.
Absent
Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.
C9-BACexp (Baloh/Lutz)
Absent
Not observed.
Absent
Not observed.
Observed
RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.
Absent
No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.
Absent
Not observed.
Absent
Not observed.
Absent
No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.
Absent
No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.
Absent
Normal lifespan.
C9orf72 Knock-out
Absent
Not observed.
Absent
Not observed.
Absent
Not observed.
Absent
Not observed.
Absent
Not observed.
Absent
Not observed.
Observed
Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.
Absent
Not observed.
Absent
Not observed.
C9ORF72(AAV)(G4C2)149
Observed
Cortical neuron loss by 6 months.
No Data
No data.
Observed
Cytoplasmic inclusions containing dipeptide repeat proteins (DPRs) derived from sense RNA seen in the cortex, hippocampus, cerebellum, and spinal cord; inclusions containing DPRs produced from antisense transcripts seen in the cortex and occasionally in the hippocampus.
Observed
Astrogliosis in the cortex by 3 months.
No Data
No data.
No Data
No data.
Observed
Deficits in the hanging wire test emerge between 3 and 6 months.
No Data
No data.
No Data
No data.
C9ORF72(AAV)(G4C2)66
Observed
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.
Absent
At 6 months, neuronal loss in the spinal cord was not detected.
Observed
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.
Observed
Astrogliosis in the cortex by 6 months.
No Data
No data.
No Data
No data.
Observed
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.
Observed
At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.
No Data
No data.
CamKII;(GR)80
Observed
Neuron loss in the cortex, beginning between 3 and 6 months of age.
No Data
No data, but note that the transgene is not expressed in these neurons.
Absent
No TDP-43 inclusions seen in mice studied up to 8 months of age.
Observed
Microgliosis and astrogliosis evident at 6 and 9 months, respectively.
No Data
No data.
No Data
No data.
Absent
No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 9 months of age.
Absent
No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 11 months of age.
No Data
No data.
Endogenous Sod1 D83G
Observed
Neuronal numbers comparable to wild-type at 15 weeks, but about 20 percent loss of upper motor neurons by 29 weeks. Neurons in layer V of the motor cortex appeared selectively vulnerable.
Observed
Neuronal numbers comparable to wild-type at 6 weeks, but loss occurred by 15 weeks. The neuronal loss then stabilized; it was not more severe at 52 weeks of age.
Absent
Not observed.
Observed
Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.
Observed
Denervation of a hindlimb muscle, the extensor digitorum longus, was detected by 52 weeks of age, and a decreased number of motor units in the EDL muscle.
No Data
Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were observed.
Observed
Both male and female mice develop a variety of progressive motor symptoms. Grip strength was reduced at 6 weeks of age. Tremors developed by about 5 months of age. Rotarod performance was impaired, at 23 weeks in females and 67 weeks in males.
Observed
Homozygous mice, both male and female, showed reduced body weight by 4 weeks of age in contrast to wild-type littermates. Loss of excessive body weight was the primary factor leading to euthanasia.
Observed
Males reach end-stage sooner than females (495 ± 22 versus 588 ± 24 days). Animals were sacrificed when weight loss exceeded 20 percent of maximum weight, in accordance with animal-use guidelines. This is likely explained by the development of hepatocellular carcinomas due to SOD1 loss of function.
FUS-R521C
Absent
No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.
Observed
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.
Observed
Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.
Observed
Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.
Observed
Reduced innervation of neuromuscular junctions in the diaphragm.
Observed
The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.
Observed
Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.
Observed
Early postnatal growth is retarded, and the mice experience progressive loss of body weight.
Observed
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.
FUSDelta14 Knock-in
No Data
No data.
Observed
No lower motor neuron loss at 3 months but 14% reduction in the number of motor neurons in lumbar spinal cord at 12 months and 20% reduction by 18 months.
Absent
No increase in the number of spinal motor neurons that contain p62- or ubiquitin-positive inclusions in aged FUSDelta14 mice compared with aged wild-type mice.
No Data
No data.
Observed
Reduction in the number of intact neuromuscular junctions (fully innervated endplates) in hindlimb lumbrical muscles by 18 months of age.
No Data
No data.
Observed
Normal motor activity at 3 months of age but impaired hindlimb function by 15 months.
No Data
No data.
Observed
Reduced survival starting at 19 months of age.
FUSΔ14 (FUSd14)
Absent
Not observed.
Absent
Not observed.
Observed
Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.
Absent
No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.
No Data
No data.
No Data
No data.
Absent
When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.
No Data
No data.
No Data
No data.
FusΔNLS
No Data
No data.
Observed
Approximately 30% reduction of motor neuron numbers in the dorsal spinal cord.
Observed
Ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.
Observed
Slight increase in oligodendrocytes in the spinal cord white matter.
Observed
Fibrillation and fasciculation potentials were observed in the gastrocnemius or tibialis anterior muscles. There was also a reduction in compound muscle action potential amplitude.
No Data
No data.
Observed
By 10 months, mice demonstrated irregular walking patterns and reduced hang time on the inverted grid test. No deficits in grip strength or rotarod performance. Paralysis was not observed.
Absent
By 22 months, no weight loss was observed.
Absent
Life span was not altered.
hFUS (+/+) (PrP-hFUS)
Absent
In the brain, overt neuronal loss was absent at end stage (~11 weeks).
Observed
By end stage (~11 weeks), homozygous mice had lost about 60 percent of α-motor neurons in the anterior horn of the lumbar spinal cord.
Observed
By end stage, cytoplasmic FUS inclusions, described as “granular” and “globular,” develop in the spinal cord of homozygous mice. Ubiquitin-positive inclusions also develop, but do not co-localize with FUS inclusions. Neurons in the brain also develop “granular” and “skein-like” FUS inclusions.
Observed
By end stage (~11 weeks), homozygous mice had microgliosis and astrogliosis in the anterior horn of the spinal cord and in the white matter of the dorsal columns. Reactive gliosis was absent in the brain, despite cytoplasmic inclusions of FUS in some neurons.
Observed
Homozygous mice had about 20 percent fewer functional motor units in the extensor digitorum longus muscle as estimated by neurophysiological assessment.
Observed
Muscle histology from end stage (~11 weeks) homozygous mice showed focal muscle atrophy in hindlimb muscles.
Observed
Homozygous mice exhibited motor symptoms at four weeks of age, starting with a tremor and mild signs of hindlimb dysfunction, including gait abnormalities. Motor symptoms progressed quickly, ultimately developing into hindlimb paralysis.
Observed
Homozygous mice fail to gain weight normally starting about four weeks of age. Their body weight declines in subsequent weeks, often precipitating euthanasia.
Observed
Homozygous mice were euthanized between 10 and 13 weeks of age when they developed severe motor impairment or lost 25 percent of their body weight. Average survival was 82 ± 12 days.
hFUS-P525L
No Data
No data.
Observed
Progressive loss of motor neurons at lumbar level 5.
Absent
No FUS inclusions were observed.
Observed
Astrocytosis and microgliosis were observed in the spinal cord.
Observed
Progressive denervation of hindlimb muscles. Decreased density of synaptic vesicles and mitochondria with normal morphologies. Altered electrophysiological properties.
Observed
Reduced fiber diameter in the tibialis anterior muscle.
Observed
Deficits in wire hang test at 360 days.
No Data
No data.
Absent
Not observed by 360 days.
hFUS-R521C
No Data
No data.
Observed
Progressive loss of motor neurons at lumbar level 5.
Absent
No FUS inclusions were observed.
Observed
Astrocytosis and microgliosis were observed in the spinal cord.
Observed
Progressive denervation of hind limb muscles.
No Data
No data.
No Data
No data.
No Data
No data.
Absent
Not observed by 360 days.
hPFN1-G118V
Observed
At 202 days, there was a decrease in the number of corticospinal neurons of the motor cortex.
Observed
Progressive loss of ventral horn neurons from 165 through 202 days of age.
Observed
Spinal cord motor neurons had TDP-43 puncta.
Observed
Astrocytosis and microgliosis were observed in the spinal cord at end stage.
Observed
Denervation of gastrocnemius muscle at end stage. Muscle action potential also had reduced amplitude.
Observed
At 165 days, hind limb muscle atrophy was observed.
Observed
Progressive motor impairments began ~ 120 days. Mice demonstrated tremors, limb clasping, muscle weakness, gait abnormalities, as well as reduced locomotion and decreased performance on the Rotarod.
Observed
Body weight peaked ~ 150 days and then progressively decreased.
Observed
Mice were sacrificed at an average of 202 days when they were unable to right themselves. Females on average reached 191 days while males attained 213 days.
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.
PFN1-C71G
Absent
No neuronal loss in the cortex but neurodegeneration in medulla.
Observed
By 4 months there was a loss of cervical motor neurons and an increase in degenerating axons.
Observed
Cytoplasmic inclusions of PFN1, ubiquitin, and p62 in motor neurons around 6 months.
Observed
Microgliosis and astrogliosis observed in the dorsal horn by 5 months.
Observed
Denervation of gastrocnemius muscle occurs by 5 months.
Observed
Muscle atrophy in lower hind limb occurs by 6 months.
Observed
By 4 months, mice began showing minor gate changes and at 5-6 months they began demonstrating progressive deficits in Rotorod performance, vertical behaviors, and grip strength.
Observed
Body weight peaked at 4-6 months and then progressively decreased.
Observed
Mice were sacrificed when they were incapable of locomotion following the paralysis of two or more limbs which occurred around 7 months of age.
PrP-hFUS (R495X)
Absent
Not observed.
Absent
Not observed.
Absent
Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.
No Data
No data.
Observed
A number of abnormalities were detected in the hindlimb musculature by electromyography (EMG). These phenotypes were detectable by 8-12 months of age and included fibrillation potentials, muscle denervation, and a reduction in the number of motor units.
No Data
No data.
Absent
Not observed.
No Data
No data.
Observed
Hemizygous mice sporadically developed intestinal swelling leading to premature death (mean survival 118 days). Homozygous mice were more severely affected (50 percent of the original cohort died around 59 days of age).
PrP-hFUS (WT)
No Data
No data.
No Data
No data.
Absent
Not observed.
No Data
No data.
Absent
Not observed.
No Data
No data.
Absent
Not observed.
No Data
No data.
Observed
Hemizygous mice die prematurely following a brief illness characterized by poor feeding. Mean survival of hemizygotes ~203 days.
SOD1 (G37R)
Absent
Upper motor neuron loss was not observed, although vacuolization occurred in brainstem neurons.
Observed
Motor neurons in the spinal cord and brainstem degenerated with overt neuronal loss in the ventral horn in some regions of the spinal cord by 19 weeks. The degenerative process involved extensive vacuolization.
Absent
Not observed.
Observed
Astrogliosis occurs in the spinal cord by 11 weeks of age, becoming more severe with age.
Observed
Denervated endplates have been observed.
Observed
Loss of motor axons, denervated endplates, atrophy of muscle fibers, and fiber type grouping observed by end-stage.
Observed
Motor impairment at 4-6 months, beginning with reduced spontaneous movement, then tremors, limb weakness, and poor grooming. Eventual paralysis of the hindlimbs.
Observed
Loss of body weight is observed.
Observed
Mice survive about 6 to 8 months.
SOD1-G85R (hybrid)
No Data
Unknown.
Observed
Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.
Observed
Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.
Observed
Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.
Observed
Denervation of muscle fibers is observed.
Observed
Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.
Observed
Progressive motor impairment generally starting around 8 months with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis within about two weeks.
Observed
Hemizygous mice start to lose weight at about 9 months of age.
Observed
End stage is characterized by paralysis at about 10 months of age.
SOD1-G93A (hybrid) (G1H)
Observed
Although outright upper motor neuron loss is absent or rare, degenerative signs (e.g., swollen neurites, Gallyas-positive aggregates, vacuoles, and neuritic spheroids) have been shown in motor regions of the cerebral cortex by five months of age.
Observed
Up to 50% loss of motor neurons in the cervical and lumbar segments of the spinal cord at end stage.
Observed
Inclusions accumulate in spinal motor neurons starting around 82 days of age. Inclusions generally take the form of spheroids or Lewy-body-like inclusions and commonly include a variety of neuronal intermediate filament proteins. TDP-43-positive inclusions are not present.
Observed
Gliosis, including the proliferation of reactive microglia and astrocytes, develops in parallel with motor neuron degeneration in the spinal cord.
Observed
Neuromuscular junctions degenerate around 47 days of age; fast-fatiguable motor neurons are affected first.
Observed
Longitudinal MRI has shown reduced muscle volume as early as 8 weeks of age. Atrophy is progressive. Skeletal muscle is affected, including limb and diaphragm.
Observed
Signs of motor impairment begin at about 3 months of age with a shaking tremor that leads to paralysis.
Observed
One of the first signs of illness is a slowing of growth and a plateauing of weight.
Observed
G1H mice reach end-stage disease by 5 months of age. Females typically survive longer than males.
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
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 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire tests.
Observed
Decreased by 48 weeks.
Observed
Approximately 50% mortality by 60 weeks of age.
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.