TDP43A315T transgenic mice express a full length human TAR DNA binding protein cDNA sequence bearing an A315T amino acid substitution, directed by a mouse prion protein promoter. These transgenic mice may be useful in applications related to the study of neuromuscular and neurodegenerative disorders such as ALS (Amyotrophic lateral sclerosis, Lou Gehrig's Disease) and frontotemporal lobar degeneration with ubiquitin aggregates.
Jeffrey L Elliott, The University of Texas Southwestern Medical CenterRead More +
TDP43A315T transgenic mice express a full-length human TAR DNA binding protein (TARDBP) cDNA containing an A315T amino acid substitution. Expression is directed by the mouse prion protein (Prnp) promoter. Hemizygotes from founder line 23 are viable and fertile. These mice display an increase in mean survival as compared with TDP43A315T transgenic mice on a STOCK background (Stock No. 016143). The data shows that hemizygous males have median survival of 125 days, while hemizygous females have median survival of 157 days. In neurons of patients with Amyotrophic lateral sclerosis (ALS), ubiquitin and TDP43 positive inclusions are observed. These mice express high levels of A315T TDP-43 in spinal cord, brainstem and brain. Specifically, levels in spinal cord are four-fold that of levels seen in non-transgenic mice. They develop a late onset progressive motor phenotype, characterized by hind limb weakness, progressive decline in grip strength, and reduction in stride length. A shift to cytosolic localization of A315T TDP-43 as well as lower molecular weight form of TDP-43 leads to earlier disease progression in these mice than in WT TDP-43 mice (Stock No. 016201). These transgenic mice may be useful in studying neuromuscular and neurodegenerative disorders such as ALS (Amyotrophic lateral sclerosis, Lou Gehrig's Disease) and frontotemporal lobar degeneration with ubiquitin aggregates.
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype of these B6SJL/F1 mice could vary from the originally described background. We may modify the strain description if necessary as published results become available.
A full-length human TAR DNA binding protein (TARDBP or TDP-43) cDNA sequence was modified to harbor the A315T amino acid substitution associated with familial ALS. This 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 B6SJLF1 oocytes and mice from founder line 23 were bred with CD1 mice to establish a TDP43A315T colony. The donating investigator maintained these mice on a mixed background. Upon arrival at The Jackson Laboratory, transgenic mice were bred with B6SJLF1/J mice (Stock No. 100012) for at least 5 generations to establish the colony.
|Expressed Gene||TARDBP, TAR DNA binding protein, human|
|Site of Expression|
|Allele Name||transgene insertion 23, Jeffrey L Elliott|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||A315T TDP-43 line 23|
|Gene Symbol and Name||Tg(Prnp-TARDBP*A315T)23Jlel, transgene insertion 23, Jeffrey L Elliott|
|Promoter||Prnp, prion protein, mouse, laboratory|
|Expressed Gene||TARDBP, TAR DNA binding protein, human|
|Strain of Origin||(C57BL/6 x SJL)F1|
|Molecular Note||The mouse promoter drives neuronal expression of the human cDNA with point mutations that result in the amino acid substitution of threonine for alanine at position 315 (A315T). This mutation was identified in human patients with amyotrophic lateral sclerosis with TARDBP proteinopathies. Four lines were established (23, 27, 35, and 61).|
|Mutations Made By|| |
Jeffrey Elliott, The University of Texas Southwestern Medical Center
Mutant mice were bred to B6SJLF1/J hybrid mice for many generations to establish this strain. When maintaining the live colony, hemizygous mice are bred with B6SJLF1/J hybrid mice (Stock No. 100012). On a mixed genetic background (CD1;C57BL/6;SJL),transgenic mice only survive up to 75 days with decreased motor function and progressive neurodegeneration.
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