Research Models

Find A Model By Name

Search Research Models

Search Results

20 Models

Name Other Names Strain Name Genetic Background Gene Mutation Modification Info Modification Disease Neuropathology Behavior/Cognition Other Phenotype Availability Primary Paper Visualization
Mouse Models (20)
ΔNLS4; tTA/TDP-ΔNLS, TDP-43-ΔNLS, tTA/ΔNLS B6;C3-Tg(tetO-TARDBP*)4Vle/J Transgene injected into fertilized eggs from C57BL/6J x C3HeJ. TARDBP These bigenic mice use the CAMKIIα promoter to drive expression of tetracycline transactivator (tTA) in forebrain neurons. The responder transgene is wild-type human TDP-43 minus the nuclear localization signal (NLS). Human TDP-43 is expressed constitutively unless suppressed by doxycycline. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Severe neuronal loss and gliosis in the dentate gyrus and deep cortical layers. Only very rare cytoplasmic aggregates of TDP-43 despite high levels of cytosolic protein. Degeneration of the corticospinal tract, but no lower motor neuron loss or muscle atrophy. A variety of motor, cognitive, and social deficits, including abnormal clasping response, impaired coordination on the Rotarod, decreased grip strength, impaired recognition and spatial memory, and decreased social behavior. Cognitive and motor impairments largely reversible in young mice following short-term transgene suppression. Downregulation of endogenous mouse TDP-43. No change in mortality up to 7 months of age. Mendelian ratios of offspring. The Jackson Lab: Stock# 014650; Live Igaz et al., 2011 Yes
rNLS8, regulatable NLS B6;C3-Tg(NEFH-tTA)8Vle Tg(tetO-TARDBP*)4Vle/J NEFH-tTA mice and tetO-hTDP-43ΔNLS line 4 mice were maintained on a mixed C57BL/6J x C3HeJ background. TARDBP These bigenic mice are the progeny of NEFH-tTA transgenic mice, in which the neurofilament heavy chain promoter drives expression of tetracycline transactivator (tTA), and tetO-hTDP-43ΔNLS (line 4) mice, which express a form of human TDP-43 lacking the nuclear localization signal in a tTA-dependent manner. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread cytoplasmic inclusions of TDP-43 in the brain and spinal cord. Ubiquitin-positive inclusions, loss of endogenous mouse nuclear TDP-43, cortical atrophy, motor neuron loss, astrogliosis, and NMJ denervation. A variety of motor impairments, including hindlimb clasping, fine tremor in forelimb and/or hindlimb, progressive loss of grip strength, and decline in coordinated movement and balance. Progressive decrease in body mass from a peak two weeks off dox. Atrophy of hindlimb muscles at end-stage. Premature death (median survival 10.3 weeks off dox). Available through The Jackson Lab as single transgenics: Stock# 025397 and Stock# 014650; Live. See also double transgenic Stock# 028412; Live Walker et al., 2015 Yes
ΔNLS-FUS x TARDBP, deltaNLS-FUS x TAR4 C57Bl/6J FUS, TARDBP FUS ΔNLS A cross between the ΔNLS-FUS and TDP-43(WT) mice. The ΔNLS-FUS line contains a transgene expressing myc-tagged human FUS lacking the nuclear localization signal, driven by the Thy1.2 promoter. The TDP-43(WT) line contains a transgene that encodes wild-type human TARDBP, driven by the Thy-1 promoter. FUS: Transgenic; TARDBP: Transgenic Amyotrophic Lateral Sclerosis The motor cortex exhibited gliosis, a loss of neurons, and DNLS-FUS aggregates positive for ubiquitin and p62.  Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test. Reduced lifespan. Available through Daisuke Ito. Shiihashi et al., 2016 Yes
Prp-TDP43A315T B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J C57BL/6J x CBA mice backcrossed to C57BL/6J. TARDBP TARDBP A315T This transgenic mouse expresses full-length human TARDBP with an N-terminal Flag tag and the A315T mutation. The transgene is driven by the mouse prion protein (PrP) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis Minimal motor neuron loss in the spinal cord and cortex (but see Espejo-Porras et al., 2015 and Zhang et al., 2016). Ubiquitin-positive aggregates in upper and lower motor neurons. Rare TDP-43 aggregates. Astrocytosis in spinal cord and cortical layer V. Hyperexcitability of somatostatin interneurons. Axonal degeneration and ~ 20% loss of NMJ innervation (gel diet). Variable. Gait abnormalities, and impaired performance on the Rotarod. Also deficits in radial arm water maze, not due to deficits in swimming speed. Behavior potentially confounded by gut phenotype.  Severe dysfunction in the intestinal tract involving degeneration of neurons in the colon resulting in reduced motility though the ileocaecal area. GI obstruction is the likely cause of death unless the diet is modified with soft food or gel diet. The Jackson Lab: Stock# 010700; Live Wegorzewska et al., 2009, Hatzipetros et al., 2014 Yes
Baloh’s TDP-43, C57BL/6-CBA TDP-43 A315T The Prp-TDP43A315T transgene was introduced into oocytes from C57BL/6J x CBA mice. TARDBP TARDBP A315T Transgene encodes full-length, human, mutant TARDBP with the A315T mutation and an N-terminal Flag tag. The mouse prion protein (PrP) promoter drives transgene expression. TARDBP: Transgenic Amyotrophic Lateral Sclerosis Upper and lower motor neuron loss. Cytoplasmic aggregates of ubiquitinated proteins in motor neurons. Cortical gliosis. No cytoplasmic aggregates of TDP-43. Gait abnormalities around three months, developing into a characteristic “swimming gait” by four to five months. Born at normal Mendelian ratios. Grossly normal up to three months. Muscle pathology at end-stage, including atrophic muscle fibers. Generally milder phenotypes in females. No longer available on a C57BL/6J x CBA background Wegorzewska et al., 2009 Yes
C57BL/6J Tardbp Tardp Q331K CRISPR/Cas9 was used to introduce the p.Q331K mutation into the mouse Tardp gene. Tardbp: Knock-In Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Unknown. Unknown. Available through Pietro Fratta or Abraham Acevedo-Arozena Fratta et al., 2018 Yes
LCDmut Tardbp M323K DBA/2J x C57BL/6J Tardbp Tardbp M323K This line was generated after screening DNA archives from two large-scale chemical mutagenesis projects (Acevedo-Arozena et al., 2008; Gondo et al., 2010) for mutations in Tardbp. Tardbp: Other Frontotemporal Dementia, Amyotrophic Lateral Sclerosis At 18 months of age, p62- and ubiquitin-positive inclusions in the ventral regions of the spinal cord, although apparently not in the cytoplasm of motor neurons. TDP-43 normally localized to the nucleus in 12-month mice. At 24 months, a 28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with control littermates. 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 and a 15 percent reduction in motor units innervating the extensor digitorum muscle. Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000110. Fratta et al., 2018 Yes
RRM2mut Tardbp F210I DBA/2J x C57BL/6J Tardbp Tardp F210I This line was generated after screening DNA archives from two large-scale chemical mutagenesis projects (Acevedo-Arozena et al., 2008; Gondo et al., 2010) for mutations in Tardbp. Tardbp: Other Frontotemporal Dementia, Amyotrophic Lateral Sclerosis No spinal motor neuron loss, no p62- or ubiquitin-positive inclusions at 2 years in heterozygotes. Grip strength normal at 2 years in heterozygotes. Homozygous mutation is embryonic lethal. Muscle force, motor unit numbers normal at 2 years in heterozygotes. Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000108. Fratta et al., 2018 Yes
Transgene injected into C3H x C57Bl/6 embryos and then crossed with C57Bl/6. TARDBP TARDBP A315T Full-length human TDP-43 with the A315T mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic inclusions of TDP-43, axonal changes, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. Age-associated cognitive and motor deficits as measured by the passive avoidance test and the Rotarod. Normal lifespan and fertility. Available through Jean-Pierre Julien Swarup et al., 2011 Yes
line 23 STOCK Tg(Prnp-TARDBP*A315T)23Jlel/J Transgene injected into fertilized hybrid B6SJLF1oocytes. Founders bred with CD1 to create hybrid CD1 and B6SJLF. TARDBP TARDBP A315T Transgene encodes full-length human TDP-43 with the A315T mutation. The mouse prion protein (Prp) promoter drives transgene expression. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal loss in the brain or spinal cord. Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Astrocytosis. Cytoplasmic aggregates of TDP-43 are largely absent, although some phospho-TDP-43 inclusions at end-stage. Progressive motor impairment characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs. Prior to motor deficits, mice exhibit increased fat storage, decreased lean muscle mass, and larger adipocytes in white fat. The Jackson Lab: Stock# 016143; Cryopreserved Stallings et al., 2010 Yes
Transgene injected into C3H x C57Bl/6 embryos. Founders backcrossed with C57Bl/6. TARDBP TARDBP G348C Full-length human TDP-43 with the G348C mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human TARDBP promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic inclusions of TDP-43 in neurons, axonal changes, denervated NMJs, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. Age-associated cognitive and motor deficits as measured by the passive-avoidance test, the Barnes maze, and the Rotarod. Impaired recovery after crush injury to the sciatic nerve (e.g., delayed recovery of motility and reduced axon regrowth). Normal lifespan and fertility. Available through Jean-Pierre Julien Swarup et al., 2011 Yes
TDP-43 M337V PrP (line 4) C57BL/6-Tg(Prnp-TARDBP*M337V)4Ptrc/J Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6. TARDBP TARDBP M337V Transgene expresses full-length human TARDBP with the M337V mutation, driven by the mouse prion protein (PrP) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal death. Microgliosis and astrogliosis. Abnormal mitochondria in the form of eosinophilic aggregates in spinal motor neurons. Widespread ubiquitination and accumulation of phospho-tau. Body tremors and gait difficulties before one month of age, leading to a “dragging” gait. An inability to right themselves precipitating euthanasia around one to two months of age. Reduced brain and body weight compared with non-Tg littermates. The Jackson Lab: Stock# 017604; Cryopreserved Xu et al., 2011 Yes
Mt-TAR6/6 Transgene injected into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP TARDBP M337V The Thy-1.2 promoter drives expression of a transgene encoding human TARDBP with the M337V mutation. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuronal loss in cortical layer V motor neurons, spinal anterior horn motor neurons, CA regions of the hippocampus, and thalamic neurons. Astrogliosis and microgliosis. Diffuse cytoplasmic ubiquitin in cortical and spinal motor neurons and hippocampus, but rare overt inclusions. Deformed mitochondria and fission deficits. Progressive motor impairment, involving a hunched posture, muscle twitches, and reduced mobility. Impaired Rotarod performance. Complete paralysis and premature death. Postnatal growth retardation and weight loss. Transgene induced downregulation in endogenous TDP-43. Increased caspase-3 expression. Ultrastructural mitochondria abnormalities. Unknown Janssens et al., 2013 Yes
Transgene introduced into C57Bl6/C3H oocytes. Founders crossed to C57/Bl6 for a minimum of four generations. TARDBP TARDBP Q331K Full-length human TDP-43 with the Q331K mutation driven by the mouse prion protein (Prp) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Age-dependent lower motor loss, gliosis, NMJ abnormalities and loss. No TDP-43 aggregates or cytoplasmic mislocalization. A variety of motor impairments starting around 3 months of age including tremor, abnormal hindlimb clasping, decreased Rotarod performance, and a later decrease in grip strength. Unknown Arnold et al., 2013 Yes
TDP-43Q331K KI (Line 52) C57Bl/6J Tardbp Tardp Q331K CRISPR/Cas9 mutagenesis was used to introduce a point mutation equivalent to human Q331K into the mouse Tardp gene. Tardbp: Knock-In Frontotemporal Dementia, Amyotrophic Lateral Sclerosis No TDP-43- or tau-positive inclusions. No apparent loss of upper or lower motor neurons, but 25% decrease in number of parvalbumin-positive neurons in frontal cortex. Attention deficits in a five-choice serial reaction time task, memory deficits in a novel-object-recognition task, deficits in a marble-burying task. No apparent motor impairments. Gene-expression and splicing differences, compared with wild-type mice, including upregulation of Tardp, and altered splicing of Tardp, Sort1, Mapt. Available from Jemeen Sreedharan or Robert H. Brown Jr. White et al., 2018 Yes
Elliott, WT TDP-43 (line 4) B6SJL-Tg(Prnp-TARDBP)4Jlel/J Transgene injected into B6SJLF1 oocytes. Founders crossed with CD1 mice. TARDBP Transgene expressing full-length, wild-type, human TDP-43 driven by the mouse prion protein (Prp) promoter. Transgene integrated on X chromosome. TARDBP: Transgenic Amyotrophic Lateral Sclerosis No overt neuronal loss in the brain or spinal cord.  Progressive motor impairment (variable penetrance) starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Relatively high TDP-43 expression in skeletal muscle. Myopathy, including variable muscle fiber size and disorganization of the muscle architecture. Ubiquitin-positive inclusions in skeletal muscle cells. Status of original hybrid unknown. This model is available on a B6SJL background through The Jackson Lab: Stock# 016201; Cryopreserved Stallings et al., 2010 Yes
Julien model, Wild-type TDP-43 Transgene injected into C3H x C57Bl/6 embryos. Founders crossed with C57Bl/6. TARDBP Full-length, wild-type, human TDP-43 driven by the endogenous human promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Some denervated NMJs, gliosis (microgliosis and astrogliosis), no overt neuronal loss or loss of axons. Mostly nuclear expression of TDP-43. Age-associated cognitive and motor deficits as measured by the passive avoidance test, Barnes maze, and Rotarod. Impaired recovery following crush injury to the sciatic nerve (e.g., delayed recovery of motility, reduced axon regrowth). Normal lifespan and fertility. Not available: extinct Swarup et al., 2011 Yes
WT-TAR4/4, WT-TAR4 B6;SJL-Tg(Thy1-TARDBP)4Singh/J Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP Transgene encodes wild-type human TARDBP, driven by the murine Thy-1 promoter. The transgene integrated at locus 6qB3 in the mouse genome and does not interrupt any known gene. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuronal loss in the brain and spinal cord, including anterior cortex, CA3 hippocampus, Purkinje cells, and spinal cord. Astrogliosis and microgliosis especially in the anterior cortex. Widespread diffuse ubiquitin in neurons of the brain and spinal cord, including cytoplasmic and nuclear inclusions, some co-labeling for TDP-43. Progressive motor impairment, starting at postnatal day 14, with an abnormal hindlimb reflex. Gait abnormalities, including reduced stride length and impaired performance on the accelerating Rotarod. Quick progression to muscle fasciculation’s and spasms, followed by paralysis and premature death. Elevated anxiety at a young age. Size and weight of homozygotes lag behind non-Tg and hemizygous littermates. The Jackson Lab: Stock# 012836; Cryopreserved Wils et al., 2010 Yes
Wild-type TDP-43 transgenic (line 3C), TDP-43PrP C57BL/6-Tg(Prnp-TARDBP)3cPtrc/J Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6. TARDBP Transgene expresses wild-type human TARDBP driven by the mouse prion protein (Prp) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal death, but degenerating neurites and axons, gliosis, and vacuolization of myelin. Abnormal aggregates of mitochondria present as eosinophilic aggregates in spinal motor neurons. Dendritic spine loss in the hippocampus. Homozygous mice develop body tremors and gait impairments leading to a “swimming gait” and severe motor deficits requiring euthanasia. Early reductions in body and brain weight in homozygous mice. Reduced dendritic spines in the hippocampus and lower mRNA levels of synaptic markers. The Jackson Lab: Stock# 016608; Cryopreserved Xu et al., 2010 Yes
WT-TAR6/6, TAR6/6 Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP Transgene encodes wild-type human TARDBP, driven by the murine Thy-1.2 promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Accumulation of transgenic and C-terminal fragments of TDP-43 in the cytoplasm, upper and lower motor neuron loss, astrogliosis, and microgliosis. Motor impairments as early as 6 weeks, reduced anxiety and disturbed nest-building behavior. Early death—average survival is 6.7 months. The CRO QPS-Austria offers research with TAR6/6 mice. Wils et al., 2010, Scherz et al., 2018 Yes

20 Visualizations

AD-related Research Models

Phenotypes Examined

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.

hTDP-43ΔNLS

Observed
  1. X
    Motor Impairment at 1

    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.

  2. X
    Cortical Neuron Loss at 4

    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.

  3. X
    Gliosis at 4

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

Absent
  • Lower Motor Neuron Loss at

    Not observed.

  • Cytoplasmic Inclusions at

    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).

  • Muscle Atrophy at

    Not observed.

  • Premature Death at

    Not observed.

No Data
  • NMJ Abnormalities at

    Unknown.

  • Body Weight at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Severe neuronal loss and gliosis in the dentate gyrus and deep cortical layers. Only very rare cytoplasmic aggregates of TDP-43 despite high levels of cytosolic protein. Degeneration of the corticospinal tract, but no lower motor neuron loss or muscle atrophy.

A variety of motor, cognitive, and social deficits, including abnormal clasping response, impaired coordination on the Rotarod, decreased grip strength, impaired recognition and spatial memory, and decreased social behavior. Cognitive and motor impairments largely reversible in young mice following short-term transgene suppression.

expand

NEFH-tTA x hTDP-43ΔNLS

Observed
  1. X
    Motor Impairment at 0

    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).

  2. X
    Cortical Neuron Loss at 0

    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.

  3. X
    Lower Motor Neuron Loss at 0

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

  4. X
    Cytoplasmic Inclusions at 0

    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.

  5. X
    NMJ Abnormalities at 0

    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.

  6. X
    Muscle Atrophy at 0

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

  7. X
    Body Weight at 0

    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.

  8. X
    Premature Death at 0

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

  9. X
    Gliosis at 0

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

Absent
No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Widespread cytoplasmic inclusions of TDP-43 in the brain and spinal cord. Ubiquitin-positive inclusions, loss of endogenous mouse nuclear TDP-43, cortical atrophy, motor neuron loss, astrogliosis, and NMJ denervation.

A variety of motor impairments, including hindlimb clasping, fine tremor in forelimb and/or hindlimb, progressive loss of grip strength, and decline in coordinated movement and balance.

expand

ΔNLS-FUS x TDP-43(WT)

Observed
  1. X
    Motor Impairment at 8

    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.

  2. X
    Cortical Neuron Loss at 52

    By 1 year, there was neuronal loss in the motor cortex.

  3. X
    Cytoplasmic Inclusions at 24

    Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

  4. X
    Body Weight at 48

    Decreased by 48 weeks.

  5. X
    Premature Death at 60

    Approximately 40% mortality by 60 weeks of age.

  6. X
    Gliosis at 52

    Microgliosis and astrocytosis were observed in the motor cortex.

Absent
  • Lower Motor Neuron Loss at

    Not observed at 1 year in the L5 anterior horn.

No Data
  • NMJ Abnormalities at

    No data.

  • Muscle Atrophy at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
FUS, TARDBP FUS ΔNLS FUS: Transgenic; TARDBP: Transgenic Amyotrophic Lateral Sclerosis

The motor cortex exhibited gliosis, a loss of neurons, and DNLS-FUS aggregates positive for ubiquitin and p62. 

Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test.

expand

TARDBP (A315T) (congenic)

Observed
  1. X
    Motor Impairment at 0

    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.

  2. X
    Cytoplasmic Inclusions at 0

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

  3. X
    NMJ Abnormalities at 0

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

  4. X
    Muscle Atrophy at 0

    Atrophy of gastrocnemius muscle (gel diet).

  5. X
    Body Weight at 0

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

  6. X
    Premature Death at 0

    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.

  7. X
    Gliosis at 0

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

Absent
  • Lower Motor Neuron Loss at

    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.

No Data
  • Cortical Neuron Loss at

    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).

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP A315T TARDBP: Transgenic Amyotrophic Lateral Sclerosis

Minimal motor neuron loss in the spinal cord and cortex (but see Espejo-Porras et al., 2015 and Zhang et al., 2016). Ubiquitin-positive aggregates in upper and lower motor neurons. Rare TDP-43 aggregates. Astrocytosis in spinal cord and cortical layer V. Hyperexcitability of somatostatin interneurons. Axonal degeneration and ~ 20% loss of NMJ innervation (gel diet).

Variable. Gait abnormalities, and impaired performance on the Rotarod. Also deficits in radial arm water maze, not due to deficits in swimming speed. Behavior potentially confounded by gut phenotype.

 

expand

TARDBP (A315T) (hybrid)

Observed
  1. X
    Motor Impairment at 12

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

  2. X
    Cortical Neuron Loss at 18

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

  3. X
    Lower Motor Neuron Loss at 19

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

  4. X
    Cytoplasmic Inclusions at 21

    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.

  5. X
    Muscle Atrophy at 20

    By end-stage, atrophic muscle fibers were observed.

  6. X
    Body Weight at 18

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

  7. X
    Premature Death at 22

    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.

  8. X
    Gliosis at 19

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

Absent
No Data
  • NMJ Abnormalities at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP A315T TARDBP: Transgenic Amyotrophic Lateral Sclerosis

Upper and lower motor neuron loss. Cytoplasmic aggregates of ubiquitinated proteins in motor neurons. Cortical gliosis. No cytoplasmic aggregates of TDP-43.

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

expand

Tardbp Q331K Knock-In

Observed
Absent
No Data
  • Motor Impairment at

    No data.

  • Cortical Neuron Loss at

    No data.

  • Lower Motor Neuron Loss at

    No data.

  • Cytoplasmic Inclusions at

    No data.

  • NMJ Abnormalities at

    No data.

  • Muscle Atrophy at

    No data.

  • Body Weight at

    No data.

  • Premature Death at

    No data.

  • Gliosis at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Tardbp Tardp Q331K Tardbp: Knock-In Frontotemporal Dementia, Amyotrophic Lateral Sclerosis

Unknown.

Unknown.

expand

Tardp LCDmut

Observed
  1. X
    Motor Impairment at 48

    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.

  2. X
    Lower Motor Neuron Loss at 96

    28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with non-transgenic littermates.

  3. X
    Cytoplasmic Inclusions at 72

    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.

  4. X
    NMJ Abnormalities at 96

    By 24 months, a 15 percent reduction in motor units innervating the extensor digitorum muscle.

Absent
  • Premature Death at

    Do not exhibit premature death, at least until 24 months of age.

No Data
  • Cortical Neuron Loss at

    No data.

  • Muscle Atrophy at

    No data.

  • Body Weight at

    No data.

  • Gliosis at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Tardbp Tardbp M323K Tardbp: Other Frontotemporal Dementia, Amyotrophic Lateral Sclerosis

At 18 months of age, p62- and ubiquitin-positive inclusions in the ventral regions of the spinal cord, although apparently not in the cytoplasm of motor neurons. TDP-43 normally localized to the nucleus in 12-month mice. At 24 months, a 28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with control littermates.

Grip strength in both male and female mice begins to decline at 12 months of age.

expand

Tardp_RRM2mut

Observed
Absent
  • Motor Impairment at

    Not observed at 2 years.

  • Lower Motor Neuron Loss at

    Not observed at 2 years.

  • Cytoplasmic Inclusions at

    Not observed at 2 years.

  • NMJ Abnormalities at

    Not observed at 2 years.

  • Premature Death at

    Homozygous mutation is embryonic lethal.

No Data
  • Cortical Neuron Loss at

    No data.

  • Muscle Atrophy at

    No data.

  • Body Weight at

    No data.

  • Gliosis at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Tardbp Tardp F210I Tardbp: Other Frontotemporal Dementia, Amyotrophic Lateral Sclerosis

No spinal motor neuron loss, no p62- or ubiquitin-positive inclusions at 2 years in heterozygotes.

Grip strength normal at 2 years in heterozygotes.

expand

TDP-43 (A315T)

Observed
  1. X
    Motor Impairment at 38

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

  2. X
    Cytoplasmic Inclusions at 43

    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.

  3. X
    Gliosis at 13

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

Absent
  • Cortical Neuron Loss at

    Not observed.

  • Lower Motor Neuron Loss at

    Not observed.

  • Premature Death at

    Not observed.

No Data
  • NMJ Abnormalities at

    Unknown.

  • Muscle Atrophy at

    Unknown.

  • Body Weight at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP A315T TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Cytoplasmic inclusions of TDP-43, axonal changes, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43.

Age-associated cognitive and motor deficits as measured by the passive avoidance test and the Rotarod.

expand

TDP-43 (A315T) (line 23)

Observed
  1. X
    Motor Impairment at 0

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

  2. X
    Cytoplasmic Inclusions at 0

    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.

  3. X
    Muscle Atrophy at 0

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

  4. X
    Body Weight at 0

    Progressive weight loss.

  5. X
    Premature Death at 0

    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.

  6. X
    Gliosis at 0

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

Absent
  • Cortical Neuron Loss at

    Not observed.

  • Lower Motor Neuron Loss at

    Not observed.

No Data
  • NMJ Abnormalities at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP A315T TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

No overt neuronal loss in the brain or spinal cord. Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Astrocytosis. Cytoplasmic aggregates of TDP-43 are largely absent, although some phospho-TDP-43 inclusions at end-stage.

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

expand

TDP-43 (G348C)

Observed
  1. X
    Motor Impairment at 36

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

  2. X
    Cytoplasmic Inclusions at 43

    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.

  3. X
    NMJ Abnormalities at 43

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

  4. X
    Gliosis at 13

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

Absent
  • Cortical Neuron Loss at

    Not observed.

  • Lower Motor Neuron Loss at

    Not observed.

  • Premature Death at

    Normal lifespan.

No Data
  • Muscle Atrophy at

    Unknown.

  • Body Weight at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP G348C TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Cytoplasmic inclusions of TDP-43 in neurons, axonal changes, denervated NMJs, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43.

Age-associated cognitive and motor deficits as measured by the passive-avoidance test, the Barnes maze, and the Rotarod.

expand

TDP-43 (M337V)

Observed
  1. X
    Motor Impairment at 3

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

     

  2. X
    Cytoplasmic Inclusions at 0

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

  3. X
    Body Weight at 4

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

     

  4. X
    Premature Death at 5

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

  5. X
    Gliosis at 0

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

Absent
  • Cortical Neuron Loss at

    Not observed.

  • Lower Motor Neuron Loss at

    Not observed.

No Data
  • NMJ Abnormalities at

    No data.

  • Muscle Atrophy at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP M337V TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

No overt neuronal death. Microgliosis and astrogliosis. Abnormal mitochondria in the form of eosinophilic aggregates in spinal motor neurons. Widespread ubiquitination and accumulation of phospho-tau.

Body tremors and gait difficulties before one month of age, leading to a “dragging” gait. An inability to right themselves precipitating euthanasia around one to two months of age.

expand

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

Observed
  1. X
    Motor Impairment at 2

    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.

  2. X
    Cortical Neuron Loss at 2

    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.

  3. X
    Lower Motor Neuron Loss at 2

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

  4. X
    Cytoplasmic Inclusions at 2

    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.

  5. X
    Body Weight at 2

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

  6. X
    Premature Death at 2

    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).

  7. X
    Gliosis at 0

    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.

Absent
No Data
  • NMJ Abnormalities at

    Unknown.

  • Muscle Atrophy at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP M337V TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Neuronal loss in cortical layer V motor neurons, spinal anterior horn motor neurons, CA regions of the hippocampus, and thalamic neurons. Astrogliosis and microgliosis. Diffuse cytoplasmic ubiquitin in cortical and spinal motor neurons and hippocampus, but rare overt inclusions. Deformed mitochondria and fission deficits.

Progressive motor impairment, involving a hunched posture, muscle twitches, and reduced mobility. Impaired Rotarod performance. Complete paralysis and premature death.

expand

TDP-43 (Q331K)

Observed
  1. X
    Motor Impairment at 13

    Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.

  2. X
    Lower Motor Neuron Loss at 8

    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.

  3. X
    NMJ Abnormalities at 43

    Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.

  4. X
    Gliosis at 43

    Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.

Absent
  • Cytoplasmic Inclusions at

    TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.

No Data
  • Cortical Neuron Loss at

    Unknown.

  • Muscle Atrophy at

    Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.

  • Body Weight at

    Unknown.

  • Premature Death at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP Q331K TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Age-dependent lower motor loss, gliosis, NMJ abnormalities and loss. No TDP-43 aggregates or cytoplasmic mislocalization.

A variety of motor impairments starting around 3 months of age including tremor, abnormal hindlimb clasping, decreased Rotarod performance, and a later decrease in grip strength.

expand

TDP-43 (Q331K) Knock-In (Line 52)

Observed
  1. X
    Cortical Neuron Loss at 20

    25% loss of parvalbumin-positive neurons at 5 months.

  2. X
    Body Weight at 32

    Increased body weight.

  3. X
    Premature Death at 0

    Mutation may be deleterious to male embryos.

Absent
  • Motor Impairment at

    Not observed.

  • Lower Motor Neuron Loss at

    Not observed.

  • Cytoplasmic Inclusions at

    Not observed.

  • NMJ Abnormalities at

    Not observed.

No Data
  • Muscle Atrophy at

    Unknown.

  • Gliosis at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Tardbp Tardp Q331K Tardbp: Knock-In Frontotemporal Dementia, Amyotrophic Lateral Sclerosis

No TDP-43- or tau-positive inclusions. No apparent loss of upper or lower motor neurons, but 25% decrease in number of parvalbumin-positive neurons in frontal cortex.

Attention deficits in a five-choice serial reaction time task, memory deficits in a novel-object-recognition task, deficits in a marble-burying task. No apparent motor impairments.

expand

TDP-43 (WT) (Elliott)

Observed
  1. X
    Motor Impairment at 0

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

  2. X
    Cytoplasmic Inclusions at 0

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

  3. X
    Muscle Atrophy at 0

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

  4. X
    Body Weight at 0

    Progressive weight loss.

  5. X
    Premature Death at 16

    The mean survival of hemizygous mice was 109 days (it is not clear if this value represents males, females, or both).

Absent
  • Cortical Neuron Loss at

    Not observed.

  • Lower Motor Neuron Loss at

    Not observed.

No Data
  • NMJ Abnormalities at

    No data.

  • Gliosis at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP: Transgenic Amyotrophic Lateral Sclerosis

No overt neuronal loss in the brain or spinal cord.

 

Progressive motor impairment (variable penetrance) starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone.

expand

TDP-43 (WT) (Julien model)

Observed
  1. X
    Motor Impairment at 42

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

  2. X
    NMJ Abnormalities at 41

    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.

  3. X
    Gliosis at 12

    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.

Absent
  • Cortical Neuron Loss at

    Not observed.

  • Lower Motor Neuron Loss at

    Not observed.

  • Cytoplasmic Inclusions at

    Primarily nuclear localization of human TDP-43.

No Data
  • Muscle Atrophy at

    No data.

  • Body Weight at

    No data.

  • Premature Death at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Some denervated NMJs, gliosis (microgliosis and astrogliosis), no overt neuronal loss or loss of axons. Mostly nuclear expression of TDP-43.

Age-associated cognitive and motor deficits as measured by the passive avoidance test, Barnes maze, and Rotarod.

expand

TDP-43 (WT) (Kumar-Singh)

Observed
  1. X
    Motor Impairment at 2

    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.

  2. X
    Cortical Neuron Loss at 3

    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.

  3. X
    Lower Motor Neuron Loss at 3

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

  4. X
    Cytoplasmic Inclusions at 3

    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.

  5. X
    Body Weight at 0

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

  6. X
    Premature Death at 3

    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.

  7. X
    Gliosis at 2

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

Absent
No Data
  • NMJ Abnormalities at

    No data.

  • Muscle Atrophy at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Neuronal loss in the brain and spinal cord, including anterior cortex, CA3 hippocampus, Purkinje cells, and spinal cord. Astrogliosis and microgliosis especially in the anterior cortex. Widespread diffuse ubiquitin in neurons of the brain and spinal cord, including cytoplasmic and nuclear inclusions, some co-labeling for TDP-43.

Progressive motor impairment, starting at postnatal day 14, with an abnormal hindlimb reflex. Gait abnormalities, including reduced stride length and impaired performance on the accelerating Rotarod. Quick progression to muscle fasciculation’s and spasms, followed by paralysis and premature death.

expand

TDP-43 (WT) (Petrucelli)

Observed
  1. X
    Motor Impairment at 3

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

  2. X
    Cytoplasmic Inclusions at 4

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

  3. X
    Body Weight at 2

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

     

  4. X
    Premature Death at 5

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

  5. X
    Gliosis at 4

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

Absent
  • Cortical Neuron Loss at

    Not observed.

  • Lower Motor Neuron Loss at

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

  • Muscle Atrophy at

    Atrophy of the gastrocnemius muscle was not observed.

No Data
  • NMJ Abnormalities at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

No overt neuronal death, but degenerating neurites and axons, gliosis, and vacuolization of myelin. Abnormal aggregates of mitochondria present as eosinophilic aggregates in spinal motor neurons. Dendritic spine loss in the hippocampus.

Homozygous mice develop body tremors and gait impairments leading to a “swimming gait” and severe motor deficits requiring euthanasia.

expand

TDP-43 (Wt-TAR6/6)

Observed
  1. X
    Motor Impairment at 6

    Progressive motor impairment; abnormal hind limb reflexes observed as early as 1.5 months.

  2. X
    Cortical Neuron Loss at 24

    Approximate 15 percent loss of layer V neurons in motor cortex at 6 months.

  3. X
    Lower Motor Neuron Loss at 12

    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.

  4. X
    Cytoplasmic Inclusions at 0

    Inclusions containing phosphorylated TDP-43 rarely observed in the nuclei and cytoplasm of spinal neurons.

  5. X
    Muscle Atrophy at 0

    Muscle wasting, particularly in flanks.

  6. X
    Body Weight at 13

    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).

  7. X
    Premature Death at 27

    Average survival is 6.7 months.

  8. X
    Gliosis at 6

    Microgliosis in cortex and spinal cord prominent at 6 months; astrogliosis in cortex and spinal cord apparent at 1.5 months.

Absent
No Data
  • NMJ Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TARDBP TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

Accumulation of transgenic and C-terminal fragments of TDP-43 in the cytoplasm, upper and lower motor neuron loss, astrogliosis, and microgliosis.

Motor impairments as early as 6 weeks, reduced anxiety and disturbed nest-building behavior.

expand

ALS-related Research Models

Sex-specific differences

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

hTDP-43ΔNLS

  • Observed
  • Absent
  • Absent
  • Observed
  • No Data
  • Absent
  • Observed
  • No Data
  • Absent

NEFH-tTA x hTDP-43ΔNLS

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

TARDBP (A315T) (congenic)

  • No Data
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

TARDBP (A315T) (hybrid)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Tardbp Q331K Knock-In

  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data

Tardp LCDmut

  • No Data
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • Observed
  • No Data
  • Absent

Tardp_RRM2mut

  • No Data
  • Absent
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent

TDP-43 (A315T)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • No Data
  • Absent

TDP-43 (A315T) (line 23)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

TDP-43 (G348C)

  • Absent
  • Absent
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • Absent

TDP-43 (M337V)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

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

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

TDP-43 (Q331K)

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • No Data

TDP-43 (Q331K) Knock-In (Line 52)

  • Observed
  • Absent
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • Observed
  • Observed

TDP-43 (WT) (Elliott)

  • Absent
  • Absent
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

TDP-43 (WT) (Julien model)

  • Absent
  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • No Data

TDP-43 (WT) (Kumar-Singh)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

TDP-43 (WT) (Petrucelli)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Absent
  • Observed
  • Observed
  • Observed

TDP-43 (Wt-TAR6/6)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

ΔNLS-FUS x TDP-43(WT)

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

ALS-related Research Models

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

hTDP-43ΔNLS

Observed

Absent

Absent

Observed

No Data

Absent

Observed

No Data

Absent

NEFH-tTA x hTDP-43ΔNLS

Observed

Observed

Observed

Observed

Observed

Observed

Observed

Observed

Observed

TARDBP (A315T) (congenic)

No Data

Absent

Observed

Observed

Observed

Observed

Observed

Observed

Observed

TARDBP (A315T) (hybrid)

Observed

Observed

Observed

Observed

No Data

Observed

Observed

Observed

Observed

Tardbp Q331K Knock-In

No Data

No Data

No Data

No Data

No Data

No Data

No Data

No Data

No Data

Tardp LCDmut

No Data

Observed

Observed

No Data

Observed

No Data

Observed

No Data

Absent

Tardp_RRM2mut

No Data

Absent

Absent

No Data

Absent

No Data

Absent

No Data

Absent

TDP-43 (A315T)

Absent

Absent

Observed

Observed

No Data

No Data

Observed

No Data

Absent

TDP-43 (A315T) (line 23)

Absent

Absent

Observed

Observed

No Data

Observed

Observed

Observed

Observed

TDP-43 (G348C)

Absent

Absent

Observed

Observed

Observed

No Data

Observed

No Data

Absent

TDP-43 (M337V)

Absent

Absent

Observed

Observed

No Data

No Data

Observed

Observed

Observed

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

Observed

Observed

Observed

Observed

No Data

No Data

Observed

Observed

Observed

TDP-43 (Q331K)

No Data

Observed

Absent

Observed

Observed

No Data

Observed

No Data

No Data

TDP-43 (Q331K) Knock-In (Line 52)

Observed

Absent

Absent

No Data

Absent

No Data

Absent

Observed

Observed

TDP-43 (WT) (Elliott)

Absent

Absent

Observed

No Data

No Data

Observed

Observed

Observed

Observed

TDP-43 (WT) (Julien model)

Absent

Absent

Absent

Observed

Observed

No Data

Observed

No Data

No Data

TDP-43 (WT) (Kumar-Singh)

Observed

Observed

Observed

Observed

No Data

No Data

Observed

Observed

Observed

TDP-43 (WT) (Petrucelli)

Absent

Absent

Observed

Observed

No Data

Absent

Observed

Observed

Observed

TDP-43 (Wt-TAR6/6)

Observed

Observed

Observed

Observed

No Data

Observed

Observed

Observed

Observed

ΔNLS-FUS x TDP-43(WT)

Observed

Absent

Observed

Observed

No Data

No Data

Observed

Observed

Observed