|
Title
|
|
|
|
TDP-43 loss-of-function causes neuronal loss due to defective steroid receptor-mediated gene program switching in **Drosophila**
| |
|
Author
|
|
|
|
| |
|
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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Cell reports
| |
|
Publication
|
|
|
|
2013
| |
|
ISSN
|
|
|
|
2211-1247
| |
|
Volume/pages
|
|
|
|
3
:1
(2013)
, p. 160-172
| |
|
ISI
|
|
|
|
000321891400018
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|