Journal
ACTA NEUROPATHOLOGICA
Volume 123, Issue 6, Pages 807-823Publisher
SPRINGER
DOI: 10.1007/s00401-012-0979-3
Keywords
Amyotrophic lateral sclerosis; Apoptosis; Frontotemporal lobar degeneration; Neurodevelopment; TDP-43; Transgenic mice
Categories
Funding
- American Federation for Aging Research
- National Institutes of Health/National Institute on Aging [P50AG16574, R01AG026251, R01AG026251-03A2, P01-AG17216-08]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS 063964-01, 5R21NS071097-02]
- Amyotrophic Lateral Sclerosis Association
- Department of Defense [USAMRMC] [PR080354]
- Mayo Clinic
- McKnight Brain Research Foundation
- Evelyn F. and William L. McKnight Brain Institute at the University of Florida
- University of Florida
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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.
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