Generation and characterization of transgenic mice conditionally expressing a cytoplasmic form of human TDP-43

IGAZ LM; SWANSON E; WINTON MJ; KWONG LK; TROJANOWSKI JQ; LEE VM

Chicago, IL, USA

Congreso; Annual Meeting of the Society For Neuroscience; 2009

Society For Neuroscience (SFN)

TAR DNA-binding protein (TDP-43) is the major disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS), thereby providing a molecular link between these two disorders. Although TDP-43 is normally a nuclear protein, it has been shown that pathological TDP-43 is redistributed and sequestered as insoluble aggregates predominantly in neuronal cytoplasmic inclusions and dystrophic neurites. Moreover, pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated and N-terminally cleaved to generate C-terminal fragments. Importantly, we previously showed that expression of TDP-43 containing a mutated nuclear localization signal (NLS) resulted in TDP-43 cytoplasmic and neuritic inclusions in cultured cells, demonstrating that perturbation of endogenous TDP-43 trafficking between the nucleus and the cytoplasm leads to aggregate formation. However, at present there are no mammalian transgenic models of TDP-43 proteinopathies available.Our goal was to produce TDP-43 transgenic mice that recapitulate key features of the human disease, such as TDP-43 neuropathology, neurodegeneration, neuron loss and cognitive deficits, which are observed in cases of FTLD-U and ALS. To circumvent the possibility of embryonic lethality and to control the timing of TDP-43-NLS expression, we took advantage of a previously described inducible system, which provides both tissue specificity and temporal regulation of gene expression in selected regions of the CNS.We report here the generation of several founder lines, the confirmation of germline transmission by outcrossing to wild-type mice, and the identification of different lines of TDP-43 transgenic mice that showed cytoplasmic TDP-43-NLS expression in multiple brain areas. Regional distribution and expression levels of TDP-43 were analyzed both by immunohistochemical and biochemical methods. Hemizygous lines were viable and showed no overt fertility impairments. We consider that this inducible animal model will lead to relevant insights into the normal biology and pathophysiology of TDP-43, which in turn will be vital in the development of targeted therapies for neurodegenerative diseases.