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TDP-43 loss-of-function causes neuronal loss due to defective steroid receptor-mediated gene program switching in Drosophila.

Authors
  • Vanden Broeck, Lies1
  • Naval-Sánchez, Marina
  • Adachi, Yoshitsugu
  • Diaper, Danielle
  • Dourlen, Pierre
  • Chapuis, Julien
  • Kleinberger, Gernot
  • Gistelinck, Marc
  • Van Broeckhoven, Christine
  • Lambert, Jean-Charles
  • Hirth, Frank
  • Aerts, Stein
  • Callaerts, Patrick
  • Dermaut, Bart
  • 1 Laboratory of Behavioral and Developmental Genetics, Center of Human Genetics, University of Leuven, B3000 Leuven, Belgium. , (Belgium)
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Jan 31, 2013
Volume
3
Issue
1
Pages
160–172
Identifiers
DOI: 10.1016/j.celrep.2012.12.014
PMID: 23333275
Source
Medline
License
Unknown

Abstract

TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.

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