Journal article
Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction
Acta Neuropathologica, Vol.123(6), pp.807-823
04/27/2012
DOI: 10.1007/s00401-012-0979-3
PMCID: PMC3359456
PMID: 22539017
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. Electronic supplementary material The online version of this article (doi:10.1007/s00401-012-0979-3) contains supplementary material, which is available to authorized users.
Details
- Title: Subtitle
- Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction
- Creators
- Ashley CannonBaoli Yang - University of IowaJoshua KnightIan M. FarnhamYongjie ZhangCharles A. WuertzerSimon D'AltonWen-lang LinMonica Castanedes-CaseyLinda RousseauBrittany ScottMichael JurasicJohn HowardXin YuRachel BaileyMatthew R. SarkisianDennis W. DicksonLeonard PetrucelliJada Lewis
- Resource Type
- Journal article
- Publication Details
- Acta Neuropathologica, Vol.123(6), pp.807-823
- Publisher
- Springer Nature
- DOI
- 10.1007/s00401-012-0979-3
- PMID
- 22539017
- PMCID
- PMC3359456
- ISSN
- 0001-6322
- eISSN
- 1432-0533
- Language
- English
- Date published
- 04/27/2012
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9983557415802771
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