These hTDP-43M337V transgenic mice express a full length mutant human TAR DNA binding protein (TARDBP or TDP-43) cDNA under the direction of a mouse prion protein promoter. The cDNA is modified such that at codon 337, a methionine to replaced by a valine(M337V). The M337V mutation is associated with increased low molecular weight fragments, neuronal apoptosis and developmental delay in chick embryos. TDP-43 is a ubiquinated protein localized to the nucleus of cells. Accumulations of TDP-43 are associated with the development of Amyotrophic lateral sclerosis (ALS). Hemizygotes are viable, fertile, and normal in size, while homozygotes are initially viable with 70% dying within the first month of life. These mice express human TDP-43M337V primarily in the nuclei of neurons throughout much of the gray matter of the spinal cord and brain, including the brainstem and cortex. Homozygotes and hemizygous express TDP-43M337V in brain at 2.7 and 1.9-fold endogenous TDP-43 levels, respectively. Endogenous TDP-43 is down-regulated in response to transgene overexpression. By 21 days of age homozygotes develop body tremors, have difficulty walking, and develop an irregular "dragging" gait. By 1 month of age, homozygous TDP-43M337V mutants are smaller than hemizygous littermates, exhibit muscle weakness and become unable to right themselves. These mice exhibit reactive gliosis, and TDP-43M337V/ubiquitin aggregates containing phosphorylated TDP-43M337V. Hemizygous mice are indistinguishable from wildtype littermates. 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.
