Acta Neuropathologica

, Volume 134, Issue 6, pp 839–850 | Cite as

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

  • Ivó H. Hernández
  • Jesús Torres-Peraza
  • María Santos-Galindo
  • Eloísa Ramos-Morón
  • M. Rosario Fernández-Fernández
  • María J. Pérez-Álvarez
  • Antonio Miranda-Vizuete
  • José J. Lucas
Original Paper

Abstract

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.

Keywords

Huntington’s disease ATF5 MCL1 ER stress UPR Neuroprotection 

Supplementary material

401_2017_1770_MOESM1_ESM.pdf (480 kb)
Supplementary material 1 (PDF 479 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Ivó H. Hernández
    • 1
    • 2
    • 3
  • Jesús Torres-Peraza
    • 1
    • 2
    • 5
  • María Santos-Galindo
    • 1
    • 2
  • Eloísa Ramos-Morón
    • 4
  • M. Rosario Fernández-Fernández
    • 1
    • 2
  • María J. Pérez-Álvarez
    • 1
    • 2
    • 3
  • Antonio Miranda-Vizuete
    • 4
  • José J. Lucas
    • 1
    • 2
  1. 1.Centro de Biología Molecular Severo Ochoa (CBMSO) CSIC/UAMMadridSpain
  2. 2.Networking Research Center on Neurodegenerative Diseases (CIBERNED)Instituto de Salud Carlos IIIMadridSpain
  3. 3.Departamento de Biología, Facultad de CienciasUniversidad Autónoma de MadridMadridSpain
  4. 4.Instituto de Biomedicina de SevillaHospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSevilleSpain
  5. 5.Gerència d’Atenció Primària del Servei de Salut de les Illes Balears (IB-SALUT)PalmaSpain

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