A Drosophila model for TDP-43 proteinopathy

Yan Li, Payal Ray, Elizabeth J. Rao, Chen Shi, Weirui Guo, Xiaoping Chen, Elvin A. Woodruff, Kazuo Fushimi, Jane Y. Wu

Research output: Contribution to journalArticle

181 Scopus citations

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 testwhether increasedexpressionofwide- typehuman TDP-43(hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressinghTDP-43invariousneuronalsubpopulations. Expressionin 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 inmushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expressioninmotor neurons led to axon swelling, reductionin axonbranches andbouton numbers, andmotor 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 expressionis sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43may contribute to the pathogenesis of TDP-43 proteinopathy.

Original languageEnglish (US)
Pages (from-to)3169-3174
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number7
DOIs
StatePublished - Feb 16 2010

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Keywords

  • Amyotrophic lateral sclerosis
  • Animal model
  • RNA binding protein

ASJC Scopus subject areas

  • General

Cite this

Li, Y., Ray, P., Rao, E. J., Shi, C., Guo, W., Chen, X., Woodruff, E. A., Fushimi, K., & Wu, J. Y. (2010). A Drosophila model for TDP-43 proteinopathy. Proceedings of the National Academy of Sciences of the United States of America, 107(7), 3169-3174. https://doi.org/10.1073/pnas.0913602107