English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/214094
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Title

The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington’s disease

AuthorsHernández, Ivó H.; Torres-Peraza, Jesús F. ; Santos-Galindo, Ramós-Morón, Eloisa; Fernández-Fernández, María R.; Pérez-Álvarez, María José ; Miranda-Vizuete, Antonio ; Lucas, José J.
KeywordsHuntington’s disease
ATF5
MCL1
ER stress
UPR
Neuroprotection
Issue Date2017
PublisherSpringer
CitationActa Neuropathologica 134: 839- 850 (2017)
AbstractActivating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti-apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia. This initially led to believe that ATF5 is not expressed in adult neurons. More recently, we reported basal neuronal ATF5 expression in adult mouse brain and its neuroprotective induction during UPR in a mouse model of status epilepticus. Here we aimed to explore whether ATF5 is also expressed by neurons in human brain both in basal conditions and in Huntington’s disease (HD), where UPR has been described to be partially impaired due to defective ATF6 processing. Apart from confirming that ATF5 is present in human adult neurons, here we report accumulation of ATF5 within the characteristic polyglutamine-containing neuronal nuclear inclusions in brains of HD patients and mice. This correlates with decreased levels of soluble ATF5 and of its antiapoptotic target MCL1. We then confirmed the deleterious effect of ATF5 deficiency in a Caenorhabditis elegans model of polyglutamine-induced toxicity. Finally, ATF5 overexpression attenuated polyglutamine-induced apoptosis in a cell model of HD. These results reflect that decreased ATF5 in HD—probably secondary to sequestration into inclusions—renders neurons more vulnerable to mutant huntingtin-induced apoptosis and that ATF5-increasing interventions might have therapeutic potential for HD.
Publisher version (URL)http://dx.doi.org/10.1007/s00401-017-1770-2
URIhttp://hdl.handle.net/10261/214094
Identifiersdoi: 10.1007/s00401-017-1770-2
issn: 1432-0533
Appears in Collections:(CBM) Artículos
Files in This Item:
File Description SizeFormat 
LucasJJ_NeuroprotectionTranscription.pdf1,57 MBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.