Published in:
Open Access
01-06-2012 | Original Paper
Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction
Authors:
Ashley Cannon, Baoli Yang, Joshua Knight, Ian M. Farnham, Yongjie Zhang, Charles A. Wuertzer, Simon D’Alton, Wen-lang Lin, Monica Castanedes-Casey, Linda Rousseau, Brittany Scott, Michael Jurasic, John Howard, Xin Yu, Rachel Bailey, Matthew R. Sarkisian, Dennis W. Dickson, Leonard Petrucelli, Jada Lewis
Published in:
Acta Neuropathologica
|
Issue 6/2012
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Abstract
Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 overexpression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies.