Research Models

ALS Mouse Models

No mouse model of ALS recapitulates the human disease perfectly, and some are better suited than others for addressing a given experimental question. By organizing phenotypic information on a variety of ALS mouse models, the visual below aims to display findings in a way that facilitates comparison, selection, and discovery.

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Sex-specific differences

26 Models Selected
  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • Gliosis
  • NMJ Abnormalities
  • Muscle Atrophy
  • Motor Impairment
  • Body Weight
  • Premature Death

C9-BAC500 (Brown model)

  • Absent
  • Absent
  • Observed
  • Absent
  • Absent
  • Unknown
  • Absent
  • Absent
  • Absent

Not observed.

Not 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.

No signs of increased activation of microglia or astrocytes in the brain or spinal cord.

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 histology has not been reported, but no overt muscle atrophy was observed.

No overt motor deficit as measured by the Rotarod and grip strength.

Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.

Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.

C9-BACexp (Baloh/Lutz model)

  • Absent
  • Absent
  • Observed
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent

Not observed.

Not 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.

No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.

Not observed.

Not observed.

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.

No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.

Normal lifespan.

C9ORF72(AAV)(G4C2)66

  • Observed
  • Absent
  • Observed
  • Observed
  • Unknown
  • Unknown
  • Observed
  • Observed
  • Unknown

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.

At 6 months, neuronal loss in the spinal cord was not detected.

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.

Astrogliosis in the cortex by 6 months.

Unknown.

Unknown.

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.

At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.

Unknown.

Endogenous Sod1 D83G

  • Observed
  • Observed
  • Absent
  • Observed
  • Observed
  • Unknown
  • Observed
  • Observed
  • 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.

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.

Not observed.

Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.

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.

Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were 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.

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.

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
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.

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.

Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.

Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.

Reduced innervation of neuromuscular junctions in the diaphragm.

The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.

Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.

Early postnatal growth is retarded, and the mice experience progressive loss of body weight.

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.

FUSΔ14 (FUSd14)

  • Absent
  • Absent
  • Observed
  • Absent
  • Unknown
  • Unknown
  • Absent
  • Unknown
  • Unknown

Not observed.

Not 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.

No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.

Unknown.

Unknown.

When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.

Unknown.

Unknown.

hFUS (+/+) (PrP-hFUS)

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

In the brain, overt neuronal loss was absent at end stage (~11 weeks).

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.

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.

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.

Homozygous mice had about 20 percent fewer functional motor units in the extensor digitorum longus muscle as estimated by neurophysiological assessment.

Muscle histology from end stage (~11 weeks) homozygous mice showed focal muscle atrophy in hindlimb muscles.

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.

Homozygous mice fail to gain weight normally starting about four weeks of age. Their body weight declines in subsequent weeks, often precipitating euthanasia.

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.

hTDP-43ΔNLS

  • Observed
  • Absent
  • Absent
  • Observed
  • Unknown
  • Absent
  • Observed
  • Unknown
  • Absent

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.

Not observed.

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).

Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.

Unknown.

Not 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.

Unknown.

Not observed.

NEFH-tTA x hTDP-43ΔNLS

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • 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.

rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.

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.

Astrogliosis develops in many brain regions, including layer V of the motor cortex.

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.

At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.

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 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.

rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.

PrP-hFUS (R495X)

  • Absent
  • Absent
  • Absent
  • Unknown
  • Observed
  • Unknown
  • Absent
  • Unknown
  • Observed

Not observed.

Not observed.

Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.

Unknown.

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.

Unknown.

Not observed.

Unknown.

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)

  • Unknown
  • Unknown
  • Absent
  • Unknown
  • Absent
  • Unknown
  • Absent
  • Unknown
  • Observed

Unknown.

Unknown.

Not observed.

Unknown.

Not observed.

Unknown.

Not observed.

Unknown.

Hemizygous mice die prematurely following a brief illness characterized by poor feeding. Mean survival of hemizygotes ~203 days.

SOD1 (G37R)

  • Absent
  • Observed
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Upper motor neuron loss was not observed, although vacuolization occurred in brainstem neurons.

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.

Not observed.

Astrogliosis occurs in the spinal cord by 11 weeks of age, becoming more severe with age.

Denervated endplates have been observed.

Loss of motor axons, denervated endplates, atrophy of muscle fibers, and fiber type grouping observed by end-stage.

Motor impairment at 4-6 months, beginning with reduced spontaneous movement, then tremors, limb weakness, and poor grooming. Eventual paralysis of the hindlimbs.

Loss of body weight is observed.

Mice survive about 6 to 8 months.

SOD1-G85R (hybrid)

  • Unknown
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Unknown.

Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.

Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.

Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.

Denervation of muscle fibers is observed.

Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.

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.

Hemizygous mice start to lose weight at about 9 months of age.

End stage is characterized by paralysis at about 10 months of age.

SOD1-G93A (hybrid) (G1H)

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • 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.

Up to 50% loss of motor neurons in the cervical and lumbar segments of the spinal cord at end stage.

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.

Gliosis, including the proliferation of reactive microglia and astrocytes, develops in parallel with motor neuron degeneration in the spinal cord.

Neuromuscular junctions degenerate around 47 days of age; fast-fatiguable motor neurons are affected first.

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.

Signs of motor impairment begin at about 3 months of age with a shaking tremor that leads to paralysis.

One of the first signs of illness is a slowing of growth and a plateauing of weight.

G1H mice reach end-stage disease by 5 months of age. Females typically surviving longer than males.

TARDBP (A315T) (congenic)

  • Unknown
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

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).

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.

Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.

Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.

Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).

Atrophy of gastrocnemius muscle (gel diet).

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.

Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.

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
  • Observed
  • Observed
  • Observed
  • Unknown
  • Observed
  • Observed
  • Observed
  • Observed

By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.

By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.

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.

By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.

Unknown.

By end-stage, atrophic muscle fibers were observed.

Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.

Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.

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.

TDP-43 (A315T)

  • Absent
  • Absent
  • Observed
  • Observed
  • Unknown
  • Unknown
  • Observed
  • Unknown
  • Absent

Not observed.

Not 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.

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

Unknown.

Unknown.

At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.

Unknown.

Not observed.

TDP-43 (A315T) (line 23)

  • Absent
  • Absent
  • Observed
  • Observed
  • Unknown
  • Observed
  • Observed
  • Observed
  • Observed

Not observed.

Not 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.

Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.

Unknown.

Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.

Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.

Progressive weight loss.

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
  • Absent
  • Observed
  • Observed
  • Observed
  • Unknown
  • Observed
  • Unknown
  • Absent

Not observed.

Not 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.

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.

Unknown.

Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.

Unknown.

Normal lifespan.

TDP-43 (M337V)

  • Absent
  • Absent
  • Observed
  • Observed
  • Unknown
  • Unknown
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.

Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.

Unknown.

Unknown.

Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”

 

By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.

 

70% mortality of homozygotes by around one month of age.

TDP-43 (M337V) (Mt-TAR6/6)

  • Observed
  • Observed
  • Observed
  • Observed
  • Unknown
  • Unknown
  • Observed
  • Observed
  • 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.

Neuronal loss was observed in the spinal cords of homozygous mice.

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.

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.

Unknown.

Unknown.

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.

Early postnatal growth retardation in homozygous mice. By day 17 their average body weight is about half that of non-Tg controls.

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 (Prp)

  • Absent
  • Absent
  • Observed
  • Observed
  • Unknown
  • Absent
  • Observed
  • Observed
  • Observed

Not observed.

Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.

Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.

Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.

Unknown.

Atrophy of the gastrocnemius muscle was not observed.

By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.

 

Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.

 

Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.

TDP-43 (Q331K)

  • Unknown
  • Observed
  • Absent
  • Observed
  • Observed
  • Unknown
  • Observed
  • Unknown
  • Unknown

Unknown.

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.

Unknown.

Unknown.

TDP-43 (WT) (Elliott model)

  • Absent
  • Absent
  • Observed
  • Unknown
  • Unknown
  • Observed
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.

Unknown.

Unknown.

An analysis of the quadriceps muscle, showed signs of myopathy, including variable muscle fiber size and disorganization of the muscle architecture.

Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.

Progressive weight loss is part of the suite of symptoms in these mice.

The mean survival of hemizygous mice was 109 days. It was not reported if this value represents, males, females or both.

TDP-43 (WT) (Julien model)

  • Absent
  • Absent
  • Absent
  • Observed
  • Observed
  • Unknown
  • Observed
  • Unknown
  • Unknown

Not observed.

Not observed.

Primarily nuclear localization of human TDP-43.

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.

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.

Unknown.

Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.

Unknown.

Unknown.

TDP-43 (WT) (WT-TAR4/4)

  • Observed
  • Observed
  • Observed
  • Observed
  • Unknown
  • Unknown
  • Observed
  • Observed
  • 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.

By day 18, homozygous mice exhibited about 25 percent loss of motor neurons in the lumbar spinal cord compared with non-Tg littermates.

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.

Astrogliosis and microgliois especially in cortical layer V of the anterior cortex, including motor and somatosensory cortex, and in the spinal cord.

Unknown.

Unknown.

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.

Size and weight of homozygous mice lag behind hemizygotes and non-Tg littermates.

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.

  • Sex-specific differences
  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • Gliosis
  • NMJ Abnormalities
  • Muscle Atrophy
  • Motor Impairment
  • Body Weight
  • Premature Death

C9-BAC500 (Brown model)

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.

Unknown

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 model)

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(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.

Unknown

Unknown.

Unknown

Unknown.

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.

Unknown

Unknown.

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.

Unknown

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.

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.

Unknown

Unknown.

Unknown

Unknown.

Absent

When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.

Unknown

Unknown.

Unknown

Unknown.

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.

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.

Unknown

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.

Unknown

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.

PrP-hFUS (R495X)

Absent

Not observed.

Absent

Not observed.

Absent

Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.

Unknown

Unknown.

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.

Unknown

Unknown.

Absent

Not observed.

Unknown

Unknown.

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)

Unknown

Unknown.

Unknown

Unknown.

Absent

Not observed.

Unknown

Unknown.

Absent

Not observed.

Unknown

Unknown.

Absent

Not observed.

Unknown

Unknown.

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)

Unknown

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 surviving longer than males.

TARDBP (A315T) (congenic)

Unknown

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.

Unknown

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.

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.

Unknown

Unknown.

Unknown

Unknown.

Observed

At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.

Unknown

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.

Unknown

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.

Unknown

Unknown.

Observed

Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.

Unknown

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.

Unknown

Unknown.

Unknown

Unknown.

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.

Unknown

Unknown.

Unknown

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 (Prp)

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.

Unknown

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 (Q331K)

Unknown

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.

Unknown

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.

Unknown

Unknown.

Unknown

Unknown.

TDP-43 (WT) (Elliott model)

Absent

Not observed.

Absent

Not observed.

Observed

Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.

Unknown

Unknown.

Unknown

Unknown.

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 is part of the suite of symptoms in these mice.

Observed

The mean survival of hemizygous mice was 109 days. It was not reported 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.

Unknown

Unknown.

Observed

Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.

Unknown

Unknown.

Unknown

Unknown.

TDP-43 (WT) (WT-TAR4/4)

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.

Unknown

Unknown.

Unknown

Unknown.

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.