| Autor: |
Lies Vanden Broeck, Marina Naval-Sánchez, Yoshitsugu Adachi, Danielle Diaper, Pierre Dourlen, Julien Chapuis, Gernot Kleinberger, Marc Gistelinck, Christine Van Broeckhoven, Jean-Charles Lambert, Frank Hirth, Stein Aerts, Patrick Callaerts, Bart Dermaut |
| Jazyk: |
angličtina |
| Rok vydání: |
2013 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 3, Iss 1, Pp 160-172 (2013) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2012.12.014 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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