Abstract |
Neuropathology involving TAR DNA binding protein-43 (TDP-43) has been identified in a wide spectrum of neurodegenerative diseases collectively named as TDP-43 proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia ( FTLD). To test whether increased expression of wide-type human TDP-43 (hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressing hTDP-43 in various neuronal subpopulations. Expression in the fly eyes of the full-length hTDP-43, but not a mutant lacking its amino-terminal domain, led to progressive loss of ommatidia with remarkable signs of neurodegeneration. Expressing hTDP-43 in mushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expression in motor neurons led to axon swelling, reduction in axon branches and bouton numbers, and motor neuron loss together with functional deficits. Thus, our transgenic flies expressing hTDP-43 recapitulate important neuropathological and clinical features of human TDP-43 proteinopathy, providing a powerful animal model for this group of devastating diseases. Our study indicates that simply increasing hTDP-43 expression is sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43 may contribute to the pathogenesis of TDP-43 proteinopathy.
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Authors | Yan Li, Payal Ray, Elizabeth J Rao, Chen Shi, Weirui Guo, Xiaoping Chen, Elvin A Woodruff 3rd, Kazuo Fushimi, Jane Y Wu |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 107
Issue 7
Pg. 3169-74
(Feb 16 2010)
ISSN: 1091-6490 [Electronic] United States |
PMID | 20133767
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- DNA-Binding Proteins
- Luminescent Proteins
- red fluorescent protein
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Topics |
- Animals
- Animals, Genetically Modified
- DNA-Binding Proteins
(metabolism)
- Disease Models, Animal
- Drosophila
- Humans
- Luminescent Proteins
(metabolism)
- Microscopy, Electron, Transmission
- Microscopy, Fluorescence
- Mushroom Bodies
(metabolism)
- Neurons
(metabolism, ultrastructure)
- Retinal Degeneration
(etiology, metabolism)
- TDP-43 Proteinopathies
(complications, metabolism)
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