Journal
JOURNAL OF NEUROSCIENCE
Volume 30, Issue 32, Pages 10851-10859Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1630-10.2010
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Funding
- Mayo Clinic Foundation
- Amyotrophic Lateral Sclerosis Association
- American Federation for Aging Research Affiliate Research
- Pacific Alzheimer Research Foundation
- Association for Frontotemporal Dementias
- National Institutes of Health/National Institute on Aging [P50AG16574, R01AG026251, 2R56AG026251-03A1, P01-AG17216-08]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS 063964-01]
- myotrophic Lateral Sclerosis Association
- Department of Defense [USAMRMC PR080354]
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Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43(PrP)) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43(PrP) mice. Finally, TDP-43(PrP) mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.
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