Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Authors

Yazi D. Ke, University of New South Wales
Annika van Hummel, University of New South Wales
Claire H. Stevens, University of New South WalesFollow
Amadeus Gladbach, University of New South Wales
Stefania Ippati, University of New South Wales
Mian Bi, University of New South Wales
Wei S. Lee, University of New South Wales
Sarah Krüger, University of New South Wales
Julia van der Hoven, University of New South Wales
Alexander Volkerling, University of New South Wales
Andre Bongers, University of New South Wales
Glenda M. Halliday, Neuroscience Research Australia
Nikolas K. Haass, University of Queensland
Matthew Kiernan, University of Sydney
Fabien Delerue, University of New South Wales
Lars M. Ittner, University of New South Wales

RIS ID

107477

Publication Details

Ke, Y. D., van Hummel, A., Stevens, C. H., Gladbach, A., Ippati, S., Bi, M., Lee, W. S., Krüger, S., van der Hoven, J., Volkerling, A., Bongers, A., Halliday, G., Haass, N. K., Kiernan, M., Delerue, F. & Ittner, L. M. (2015). Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS. Acta Neuropathologica, 130 (5), 661-678.

Abstract

The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43 A315T , with controlled neuronal over-expression. Constitutive expression of human TDP-43 A315T resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43 A315T brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43 A315T expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43 A315T mice are at least in part a direct and transient effect of the presence of TDP-43 A315T . Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.