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- Title
Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction.
- Authors
Cannon, Ashley; Yang, Baoli; Knight, Joshua; Farnham, Ian; Zhang, Yongjie; Wuertzer, Charles; D'Alton, Simon; Lin, Wen-lang; Castanedes-Casey, Monica; Rousseau, Linda; Scott, Brittany; Jurasic, Michael; Howard, John; Yu, Xin; Bailey, Rachel; Sarkisian, Matthew; Dickson, Dennis; Petrucelli, Leonard; Lewis, Jada
- 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.
- Subjects
NEURONS; UBIQUITIN; DNA-binding proteins; PROSENCEPHALON; LABORATORY mice
- Publication
Acta Neuropathologica, 2012, Vol 123, Issue 6, p807
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-012-0979-3