The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington’s disease
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Activating 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.
KeywordsHuntington’s disease ATF5 MCL1 ER stress UPR Neuroprotection
This work was supported by CiberNed-ISCIII collaborative Grants PI2013/09-2 and PI2015-2/06-3 and by grants from Spanish Ministry of Economy and Competitiveness (MINECO): SAF2009-08233 and SAF2015-65371-R to JJL, by Fundación BBVA and by Fundación Ramón Areces. Human tissue was obtained from Institute of Neuropathology (HUB-ICO-IDIBELL) Brain Bank, the Neurological Tissue Bank of the IDIBAPS Biobank, the Banco de Tejidos Fundación CIEN, and the Netherlands Brain Bank. We thank Prof. Keith Blackwell for providing the LD1325 C. elegans strain. We also thank excellent technical assistance by Miriam Lucas and by the following core facilities: CBMSO-Genomics and Massive Sequencing and CBMSO-Animal Facility.
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Conflict of interest
The authors declare that they have no conflict of interest.
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