Journal
CELL REPORTS
Volume 3, Issue 1, Pages 160-172Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2012.12.014
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Funding
- Agency for Innovation by Science and Technology in Flanders (IWT)
- Foundation for Research Flanders (FWO) in Belgium
- Foundation for Alzheimer Research (SAO/FRMA)
- FWO [G.0704.11N]
- VIB Technology Watch Team in Belgium
- Etat Region Nord/Pas-de-Calais in France [11005007]
- VIB
- Interuniversity Attraction Poles program of the Belgian Science Policy Office (BELSPO) [P6/43]
- KU Leuven in Belgium [CREA/10/014 and PF/10/016]
- Foundation Against Cancer [2010-154]
- Medical Research Council
- Royal Society, UK
- Thierry Latran Foundation
- Motor Neurone Disease Association
- Methusalem program of the Flemish Government
- Alzheimers Research UK [ARUK-PhD2012-18] Funding Source: researchfish
- Medical Research Council [G0701498] Funding Source: researchfish
- MRC [G0701498] Funding Source: UKRI
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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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