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.
Similar content being viewed by others
References
Angelastro JM, Canoll PD, Kuo J, Weicker M, Costa A, Bruce JN, Greene LA (2006) Selective destruction of glioblastoma cells by interference with the activity or expression of ATF5. Oncogene 25:907–916
Angelastro JM, Ignatova TN, Kukekov VG, Steindler DA, Stengren GB, Mendelsohn C, Greene LA (2003) Regulated expression of ATF5 is required for the progression of neural progenitor cells to neurons. J Neurosci 23:4590–4600
Angelastro JM, Mason JL, Ignatova TN, Kukekov VG, Stengren GB, Goldman JE, Greene LA (2005) Downregulation of activating transcription factor 5 is required for differentiation of neural progenitor cells into astrocytes. J Neurosci 25:3889–3899
Caccamo DV, Herman MM, Frankfurter A, Katsetos CD, Collins VP, Rubinstein LJ (1989) An immunohistochemical study of neuropeptides and neuronal cytoskeletal proteins in the neuroepithelial component of a spontaneous murine ovarian teratoma. Primitive neuroepithelium displays immunoreactivity for neuropeptides and neuron-associated beta-tubulin isotype. Am J Pathol 135:801–813
Ciaccio NA, Laurence JS (2009) Effects of disulfide bond formation and protein helicity on the aggregation of activating transcription factor 5. Mol Pharm 6:1205–1215
Ciaccio NA, Reynolds TS, Middaugh CR, Laurence JS (2012) Influence of the valine zipper region on the structure and aggregation of the basic leucine zipper (bZIP) domain of activating transcription factor 5 (ATF5). Mol Pharm 9:3190–3199
Cortes CJ, La Spada AR (2014) The many faces of autophagy dysfunction in Huntington’s disease: from mechanism to therapy. Drug Discov Today 19:963–971
Chiang MC, Chen HM, Lee YH, Chang HH, Wu YC, Soong BW, Chen CM, Wu YR, Liu CS, Niu DM et al (2007) Dysregulation of C/EBPalpha by mutant huntingtin causes the urea cycle deficiency in Huntington’s disease. Hum Mol Genet 16:483–498
Das I, Krzyzosiak A, Schneider K, Wrabetz L, D’Antonio M, Barry N, Sigurdardottir A, Bertolotti A (2015) Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science (New York, NY) 348:239–242
Dluzen D, Li G, Tacelosky D, Moreau M, Liu DX (2011) BCL-2 is a downstream target of ATF5 that mediates the prosurvival function of ATF5 in a cell type-dependent manner. J Biol Chem 286:7705–7713
Fernandez-Fernandez MR, Ferrer I, Lucas JJ (2011) Impaired ATF6alpha processing, decreased Rheb and neuronal cell cycle re-entry in Huntington’s disease. Neurobiol Dis 41:23–32
Ferraz RC, Camara H, De-Souza EA, Pinto S, Pinca AP, Silva RC, Sato VN, Castilho BA, Mori MA (2016) IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans. BMC Biol 14:87. doi:10.1186/s12915-016-0301-2
Fujita K, Nakamura Y, Oka T, Ito H, Tamura T, Tagawa K, Sasabe T, Katsuta A, Motoki K, Shiwaku H et al (2013) A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases. Nat Commun 4:1816
Greene LA, Lee HY, Angelastro JM (2009) The transcription factor ATF5: role in neurodevelopment and neural tumors. J Neurochem 108:11–22
Hai T, Hartman MG (2001) The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene 273:1–11
Hatano M, Umemura M, Kimura N, Yamazaki T, Takeda H, Nakano H, Takahashi S, Takahashi Y (2013) The 5′-untranslated region regulates ATF5 mRNA stability via nonsense-mediated mRNA decay in response to environmental stress. FEBS J 280:4693–4707
Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102
Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15:233–249
Izumi S, Saito A, Kanemoto S, Kawasaki N, Asada R, Iwamoto H, Oki M, Miyagi H, Ochi M, Imaizumi K (2012) The endoplasmic reticulum stress transducer BBF2H7 suppresses apoptosis by activating the ATF5-MCL1 pathway in growth plate cartilage. J Biol Chem 287:36190–36200
Karpel-Massler G, Horst BA, Shu C, Chau L, Tsujiuchi T, Bruce JN, Canoll P, Greene LA, Angelastro JM, Siegelin MD (2016) A synthetic cell-penetrating dominant-negative ATF5 peptide exerts anticancer activity against a broad spectrum of treatment-resistant cancers. Clin Cancer Res 22:4698–4711
Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530
Li JY, Popovic N, Brundin P (2005) The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies. NeuroRx J Am Soc Exp NeuroTher 2:447–464. doi:10.1602/neurorx.2.3.447
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506
Mason JL, Angelastro JM, Ignatova TN, Kukekov VG, Lin G, Greene LA, Goldman JE (2005) ATF5 regulates the proliferation and differentiation of oligodendrocytes. Mol Cell Neurosci 29:372–380
Maynard CJ, Bottcher C, Ortega Z, Smith R, Florea BI, Diaz-Hernandez M, Brundin P, Overkleeft HS, Li JY, Lucas JJ et al (2009) Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment. Proc Natl Acad Sci USA 106:13986–13991
McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y, Paulson H, Sobue G et al (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9:2197–2202
Monaco SE, Angelastro JM, Szabolcs M, Greene LA (2007) The transcription factor ATF5 is widely expressed in carcinomas, and interference with its function selectively kills neoplastic, but not nontransformed, breast cell lines. Int J Cancer 120:1883–1890
Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA et al (2012) Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. Nature 485:507–511
Morley JF, Brignull HR, Weyers JJ, Morimoto RI (2002) The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci USA 99:10417–10422
Naranjo JR, Zhang H, Villar D, Gonzalez P, Dopazo XM, Moron-Oset J, Higueras E, Oliveros JC, Arrabal MD, Prieto A et al (2016) Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease. J Clin Investig 126:627–638
Nishizawa M, Nagata S (1992) cDNA clones encoding leucine-zipper proteins which interact with G-CSF gene promoter element 1-binding protein. FEBS Lett 299:36–38
Okazawa H (2003) Polyglutamine diseases: a transcription disorder? Cell Mol Life Sci 60:1427–1439
Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621
Ortega Z, Diaz-Hernandez M, Lucas JJ (2007) Is the ubiquitin-proteasome system impaired in Huntington’s disease? Cell Mol Life Sci 64:2245–2257
Persengiev SP, Devireddy LR, Green MR (2002) Inhibition of apoptosis by ATFx: a novel role for a member of the ATF/CREB family of mammalian bZIP transcription factors. Genes Dev 16:1806–1814
Reijonen S, Putkonen N, Norremolle A, Lindholm D, Korhonen L (2008) Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins. Exp Cell Res 314:950–960
Sheng Z, Li L, Zhu LJ, Smith TW, Demers A, Ross AH, Moser RP, Green MR (2010) A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications. Nat Med 16:671–677
Shimizu YI, Morita M, Ohmi A, Aoyagi S, Ebihara H, Tonaki D, Horino Y, Iijima M, Hirose H, Takahashi S et al (2009) Fasting induced up-regulation of activating transcription factor 5 in mouse liver. Life Sci 84:894–902
Stewart DP, Koss B, Bathina M, Perciavalle RM, Bisanz K, Opferman JT (2010) Ubiquitin-independent degradation of antiapoptotic MCL-1. Mol Cell Biol 30:3099–3110. doi:10.1128/MCB.01266-09
Stiernagle T (2006) Maintenance of C. elegans. In: WormBook, The C. elegans Research Community, eds., pp 1–11. doi:10.1895/wormbook.1.101.1. http://www.wormbook.org
Torres-Peraza JF, Engel T, Martin-Ibanez R, Sanz-Rodriguez A, Fernandez-Fernandez MR, Esgleas M, Canals JM, Henshall DC, Lucas JJ (2013) Protective neuronal induction of ATF5 in endoplasmic reticulum stress induced by status epilepticus. Brain 136:1161–1176
Tsaytler P, Harding HP, Ron D, Bertolotti A (2011) Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science (New York, NY) 332:91–94
Uekusa H, Namimatsu M, Hiwatashi Y, Akimoto T, Nishida T, Takahashi S, Takahashi Y (2009) Cadmium interferes with the degradation of ATF5 via a post-ubiquitination step of the proteasome degradation pathway. Biochem Biophys Res Commun 380:673–678
Vidal R, Caballero B, Couve A, Hetz C (2011) Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington’s disease. Curr Mol Med 11:1–12
Vinson C, Myakishev M, Acharya A, Mir AA, Moll JR, Bonovich M (2002) Classification of human B-ZIP proteins based on dimerization properties. Mol Cell Biol 22:6321–6335
Wang H, Lin G, Zhang Z (2007) ATF5 promotes cell survival through transcriptional activation of Hsp27 in H9c2 cells. Cell Biol Int 31:1309–1315
Watatani Y, Ichikawa K, Nakanishi N, Fujimoto M, Takeda H, Kimura N, Hirose H, Takahashi S, Takahashi Y (2008) Stress-induced translation of ATF5 mRNA is regulated by the 5′-untranslated region. J Biol Chem 283:2543–2553
Watatani Y, Kimura N, Shimizu YI, Akiyama I, Tonaki D, Hirose H, Takahashi S, Takahashi Y (2007) Amino acid limitation induces expression of ATF5 mRNA at the post-transcriptional level. Life Sci 80:879–885
Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, Wek RC (2008) Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem 283:7064–7073
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Hernández, I.H., Torres-Peraza, J., Santos-Galindo, M. et al. The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington’s disease. Acta Neuropathol 134, 839–850 (2017). https://doi.org/10.1007/s00401-017-1770-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-017-1770-2