Strain Name:

B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J

Stock Number:

010700

Availability:

Under Development for Distribution Colony

To register your interest in this strain go to the Strain Interest Form.
Prp-TDP43A315T transgenic mice express a mutant human TAR DNA binding protein cDNA harboring an amino acid substitution associated with familial ALS. Hemizygous mice develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates. These transgenic mice may be useful in studying neuromuscular and neurodegenerative disorders such as ALS (Lou Gehrig's Disease) and frontotemporal lobar degeneration with ubiquitin aggregates.

Description

Strain Information

Type Congenic; Mutant Strain; Transgenic;
Additional information on Genetically Engineered and Mutant Mice.
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Additional information on Congenic nomenclature.
Specieslaboratory mouse
 
Donating Investigator Robert Baloh,   Washington University School of Medicine

Description
Mice hemizygous for this Prp-TDP43A315T transgene are viable, fertile, and express a mutant human TAR DNA binding protein (TARDBP or TDP-43) cDNA harboring an N-terminal Flag tag and an A315T amino acid substitution that is associated with familial Amyotrophic Lateral Sclerosis (ALS). Expression is directed throughout the nervous system by mouse prion protein (PrP or Prnp) promoter/enhancer regions. Hemizygous mice develop a progressive gait disorder around 3-4 months of age, and die around 5 months of age. This progressive and fatal neurodegenerative disease is reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U). Specifically, hemizygous mice accumulate pathologic aggregates of ubiquitinated proteins only in specific neuronal populations, including frontal cortex layer V pyramidal neurons and spinal motor neurons with activation of local astrocytes and microglia. Loss of both upper and lower motor neurons is also observed. TDP-43 aggregates are not reported in the cytoplasm. The donating investigator has not attempted to make homozygous mice, and also reports that mice are black or agouti.

Development
A full-length human TAR DNA binding protein (TARDBP or TDP-43) cDNA sequence was modified to harbor an N-terminal Flag tag immediately after the start methionine and the A315T amino acid substitution associated with familial ALS. This Flag-TDP43A315T sequence was inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene at two unique XhoI sites in the Mo-Prp.Xho plasmid vector (ATCC#JHU-2). The resulting Prp-TDP43A315T transgene was microinjected into oocytes from hybrid C57BL/6J x CBA mice and a single Prp-TDP43A315T founder line was established (founder line 95). These mice were then backcrossed to C57BL/6J inbred mice for five generations prior to arrival at The Jackson Laboratory. The donating investigator reports that mice are black or agouti. Upon arrival, transgenic mice were bred with C57BL/6J inbred mice (Stock No. 000664) to establish the colony.

Control Information

  Control
   Noncarrier
   000664 C57BL/6J
 
  Considerations for Choosing Controls

Related Strains

View Strains carrying other alleles of Prnp     (20 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms
      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.

Tg(Prnp-TARDBP*A315T)95Balo/0

        involves: C57BL/6 * CBA
  • life span-post-weaning/aging
  • premature death (MGI Ref ID J:153197)
    • average survival is 154 days; at end-stage, mice die spontaneously or are euthanized when they lose righting reflex or can no longer obtain food and water
  • growth/size phenotype
  • weight loss (MGI Ref ID J:153197)
    • mice begin losing weight around 4.5 months of age
  • behavior/neurological phenotype
  • abnormal gait (MGI Ref ID J:153197)
    • at 3-4 months mice develop abnormal gait; around 4.5 months, mice exhibit a "swimming" gait when they lose ability to support their body weight but still use their limbs for propulsion to slide on their stomachs
  • nervous system phenotype
  • abnormal neuron morphology (MGI Ref ID J:153197)
    • late-stage mice have cytoplasmic accumulation of ubiquinated proteins in neurons of cortical layer 5; these neurons are prominent in the motor cortex and are also present in orbital, cingulated, sensory and other cortical regions
    • no ubiquinated protein aggregates are observed in the caudate/putamen, substantia nigra, thalamus or other structures at any stage
    • decreased motor neuron number (MGI Ref ID J:153197)
      • in end-stage mice, about a 20% loss of spinal motor neurons is observed
    • neuron degeneration (MGI Ref ID J:153197)
      • neuron loss in cortical layer 5
      • motor neuron degeneration (MGI Ref ID J:153197)
        • fewer axons are observed in the lower thoracic spinal cord with numerous degenerating axons being seen in dorsal corticospinal tract and lateral columns
        • femoral motor and sensory nerves shows loss of axons with ongoing axonal degeneration in the motor branch
  • abnormal spinal cord morphology (MGI Ref ID J:153197)
    • fewer axons are observed in the lower thoracic spinal cord with numerous degenerating axons being seen in dorsal corticospinal tract and lateral columns
    • abnormal spinal cord ventral horn morphology (MGI Ref ID J:153197)
      • presence of ubiquitinated protein accumulations is detected preferentially in large neurons of the dorsal horn as well as scattered interneurons
    • decreased motor neuron number (MGI Ref ID J:153197)
      • in end-stage mice, about a 20% loss of spinal motor neurons is observed
  • astrocytosis (MGI Ref ID J:153197)
    • activation of astrocytes is detected in layer 5 with reactive astrocytosis seen around degenerating neurons
  • muscle phenotype
  • abnormal muscle electrophysiology (MGI Ref ID J:153197)
    • electromyography in end-stage mice shows numerous fibrillation potentials indicative of loss of muscle fiber innervation and fasciculations, which are spontaneous firing of motor units often seen with human motor neuron diseases; in presymptomatic and early-stage mice, electromyography is normal
  • abnormal skeletal muscle morphology (MGI Ref ID J:153197)
    • end-stage mice have scattered and grouped atrophic muscle fibers, characteristic of muscle denervation
    • abnormal skeletal muscle fiber morphology (MGI Ref ID J:153197)
      • atrophic muscle fibers are observed in end-stage mice
  • muscle weakness (MGI Ref ID J:153197)
    • around 4.5 months, mice can no longer support their body weight
View Research Applications

Research Applications
This mouse can be used to support research in many areas including:

Mouse/Human Gene Homologs
amyotrophic lateral sclerosis (ALS)

Neurobiology Research
Amyotrophic Lateral Sclerosis (ALS)
Astrocyte Defects
Ataxia (Movement) Defects
Neurodegeneration
Neuromuscular Defects

Genes & Alleles

Gene & Allele Information

 
Allele Symbol Tg(Prnp-TARDBP*A315T)95Balo
Allele Name transgene insertion 95, Robert Baloh
Allele Type Transgenic (random, expressed)
Common Name(s) Prp-TDP43-A315T; Prp-TDP43A315T;
Mutation Made By Robert Baloh,   Washington University School of Medicine
Strain of OriginC57BL/6 x CBA
Expressed Gene TARDBP, TAR DNA binding protein, human
Promoter Prnp, prion protein, mouse, laboratory
Molecular Note The construct contains the full-length human TAR DNA binding protein (TARDBP or TDP-43) cDNA sequence that was modified to harbor an N-terminal Flag tag immediately after the start methionine and the A315T amino acid substitution associated with familial ALS inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene. The Prp-TDP43A315T transgene was microinjected into oocytes from hybrid C57BL/6J x CBA mice and a single Prp-TDP43A315T founder line was established (founder line 95). [MGI Ref ID J:153197]
 
 

Genotyping

Genotyping Information

Genotyping Protocols

Tg(Prnp-TARDBP*A315T), Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References

Selected Reference(s)

Wegorzewska I; Bell S; Cairns NJ; Miller TM; Baloh RH. 2009. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A :. [PubMed: 19833869]  [MGI Ref ID J:153197]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, hemizygous carriers may be bred with wildtype (noncarrier) mice from the colony or C57BL/6J inbred mice (Stock No. 000664). The donating investigator has not attempted to make homozygous mice, and also reports that mice are black or agouti.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

 

This strain is currently Under Development for Production.
To register your interest in this strain go to the Strain Interest Form.

Estimated Available for Sale Date:

Please note: Estimated available for sale dates are provided to keep customers better informed on strains under development. Please note that our Colony Managers routinely monitor the target date and edit it based on breeding performance and other factors. The length of time it takes to make a new strain available for sale depends on genotype, age, number of animals sent by the Donating Investigator, breeding performance, additional strain development (backcrossing, making homozygous), and anticipated demand for the strain/interest registered.

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Supply Details

Standard SupplyUnder Development for Distribution Colony
Supply Notes

Control Information

  Control
   Noncarrier
   000664 C57BL/6J
 
  Considerations for Choosing Controls
  USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
  International - Control Pricing Information for Genetically Engineered Mutant Strains.

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