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A Drosophila model for TDP-43 proteinopathy.

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.
AuthorsYan Li, Payal Ray, Elizabeth J Rao, Chen Shi, Weirui Guo, Xiaoping Chen, Elvin A Woodruff 3rd, Kazuo Fushimi, Jane Y Wu
JournalProceedings 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
PMID20133767 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA-Binding Proteins
  • Luminescent Proteins
  • red fluorescent protein
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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