Prp-TDP-43Q331K line 103 transgenic mice express a myc-tagged, human TAR DNA binding protein cDNA sequence modified to have the ALS-linked Q331K mutation (huTDP-43*Q331K), all under the direction of the mouse prion protein promoter (PrP). As expected for the PrP promoter, transgene expression is confined primarily to central nervous system (brain and spinal cord), with very low to no expression in other tested tissues (testis not examined). Anti-myc antibody staining shows huTDP-43*Q331K accumulation in the nuclei of neurons as well as glial cells of the spinal cord and brain, with a corresponding downregulation of endogenous mouse TDP-43. The transgene is flanked by loxP sites, allowing it to be removed by introduction of Cre recombinase if desired. The phenotype below describes Prp-TDP-43Q331K transgenic mice from founder line 103 (Prp-TDP-43Q331K [~1.5x]).
The Prp-TDP-43Q331K [~1.5x] mice have moderate overexpression levels in total TDP-43 mRNA/protein, with an ~2.5-fold increase in total TDP-43 expression (huTDP-43*Q331K levels ~1.5-fold greater) compared to endogenous TDP-43 in non-transgenic mice. By three months of age, Prp-TDP-43Q331K [~1.5x] mice develop adult-onset motor dysfunction (as measured by rotarod performance) accompanied by a loss of hindlimb-grip strength and the appearance of muscle fasciculations. Pathologically, Prp-TDP-43Q331K [~1.5x] mice demonstrate ~30% loss of L5 motor axons and 30-45% loss of lower motor neurons by ten months of age (earlier timepoints not yet tested; May 2012). Of note, this latter phenotype is in contrast to Dr. Robert Baloh's Prp-TDP43A315T transgenic mice that primarily display a loss of upper motor neurons (Stock No. 010700). Also note, this is in contrast to the founder line with low huTDP-43*Q331K overexpression (Prp-TDP-43Q331K-low line 109; Stock No. 017930), that do not exhibit loss of motor axons or neurons.
