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

177 Citations (Scopus)

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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aspartyl-arginyl-valyl-tyrosyl-isoleucyl-histidyl-prolyl-phenylalanyl-histidyl-leucyl-valyl-isoleucyl-histidine
DNA-Binding Proteins
Diptera
Axons
Neurons
Drosophila TBPH protein
Neurodegenerative Diseases

Keywords

  • Amyotrophic lateral sclerosis
  • Animal model
  • RNA binding protein

ASJC Scopus subject areas

  • General

Cite this

A Drosophila model for TDP-43 proteinopathy. / Li, Yan; Ray, Payal; Rao, Elizabeth J.; Shi, Chen; Guo, Weirui; Chen, Xiaoping; Woodruff, Elvin A.; Fushimi, Kazuo; Wu, Jane Y.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 7, 16.02.2010, p. 3169-3174.

Research output: Contribution to journalArticle

Li, Y, Ray, P, Rao, EJ, Shi, C, Guo, W, Chen, X, Woodruff, EA, Fushimi, K & Wu, JY 2010, 'A Drosophila model for TDP-43 proteinopathy', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 7, pp. 3169-3174. https://doi.org/10.1073/pnas.0913602107
Li, Yan ; Ray, Payal ; Rao, Elizabeth J. ; Shi, Chen ; Guo, Weirui ; Chen, Xiaoping ; Woodruff, Elvin A. ; Fushimi, Kazuo ; Wu, Jane Y. / A Drosophila model for TDP-43 proteinopathy. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 7. pp. 3169-3174.
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