The Unfolded Protein Response in the Human Infant Brain and Dysregulation Seen in Sudden Infant Death Syndrome (SIDS).

Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE

Original Publication: Clifton, NJ : Humana Press, c1987-

Sudden Infant Death*; Cerebellum/*metabolism ; Dorsal Raphe Nucleus/*metabolism ; Endoplasmic Reticulum Stress/*physiology ; Unfolded Protein Response/*physiology; Activating Transcription Factor 6 ; Endoplasmic Reticulum/metabolism ; Endoribonucleases/metabolism ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Orexins/metabolism ; Patient Care ; Phosphorylation ; Protein Serine-Threonine Kinases/metabolism ; Risk Factors

Low orexin levels in the hypothalamus, and abnormal brainstem expression levels of many neurotransmitter and receptor systems in infants who died suddenly during a sleep period and diagnosed as sudden infant death syndrome (SIDS), may be linked to abnormal protein unfolding. We studied neuronal expression of the three unfolded protein response (UPR) pathways in the human infant brainstem, hypothalamus, and cerebellum: activating transcription factor 6 (ATF6), phosphorylated inositol-requiring enzyme 1 (IRE1), and phosphorylated protein-kinase (PKR)-like endoplasmic reticulum (ER) kinase (pPERK). Percentages of positively stained neurons were examined via immunohistochemistry and compared between SIDS (n = 28) and non-SIDS (n = 12) infant deaths. Further analysis determined the effects of the SIDS risk factors including cigarette smoke exposure, bed-sharing, prone sleeping, and an upper respiratory tract infection (URTI). Compared to non-SIDS, SIDS infants had higher ATF6 in the inferior olivary and hypoglossal nuclei of the medulla, higher pIRE1 in the dentate nucleus of the cerebellum, and higher pPERK in the cuneate nucleus and hypothalamus. Infants who were found prone had higher ATF6 in the hypoglossal and the locus coeruleus of the pons. Infants exposed to cigarette smoke had higher ATF6 in the vestibular and cuneate nuclei of the medulla. Infants who were bed-sharing had higher pPERK in the dorsal raphe nuclei of the pons and the Purkinje cells of the cerebellum. This study indicates that subgroups of SIDS infants, defined by risk exposure, had activation of the UPR in several nuclei relating to proprioception and motor control, suggesting that the UPR underlies the neuroreceptor system changes responsible for these physiological functions, leading to compromise in the pathogenesis of SIDS.

Krous HF, Beckwith JB, Byard RW, Rognum TO, Bajanowski T, Corey T, Cutz E, Hanzlick R et al (2004) Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach. Pediatrics. Am Acad Pediatr 114(1):234–238. https://doi.org/10.1542/PEDS.114.1.234. (PMID: 10.1542/PEDS.114.1.23415231934)
Australian Bureau of Statistics (2016) 3303.0 - Causes of Death, Australia, 2016. Available at: https://www.abs.gov.au/AUSSTATS/[email protected]/Previousproducts/3303.0TechnicalNote22016?opendocument&tabname=Notes&prodno=3303.0&issue=2016&num=&view = (Accessed: 19 Feb 2020).
Hunt CE (1992) The cardiorespiratory control hypothesis for sudden infant death syndrome. Clin Perinatol. Elsevier 19:757–771. https://doi.org/10.1016/s0095-5108(18)30429-9. (PMID: 10.1016/s0095-5108(18)30429-91464189)
Franco P, Kato I, Richardson HL, Yang JSC, Montemitro E, Horne RSC (2010) Arousal from sleep mechanisms in infants. Sleep Med 11:603–614. https://doi.org/10.1016/j.sleep.2009.12.014. (PMID: 10.1016/j.sleep.2009.12.01420630799)
Hunt NJ, Waters KA, Rodriguez ML, Machaalani R (2015) Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome. Acta Neuropathol 130(2):185–198. https://doi.org/10.1007/s00401-015-1437-9. (PMID: 10.1007/s00401-015-1437-925953524)
Hunt NJ, Waters KA, Machaalani R (2017) Promotion of the unfolding protein response in orexin/dynorphin neurons in sudden infant death syndrome (SIDS): elevated pPERK and ATF4 expression. Mol Neurobiol 54(9):7171–7185. https://doi.org/10.1007/s12035-016-0234-3. (PMID: 10.1007/s12035-016-0234-327796753)
Sanderson TH, Gallaway M, Kumar R (2015) Unfolding the unfolded protein response: unique insights into brain ischemia. Int J Mol Sci 16(4):7133–7142. https://doi.org/10.3390/ijms16047133. (PMID: 10.3390/ijms16047133258304814425008)
Doyle KM et al (2011) Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med. John Wiley & Sons, Ltd (10.1111) 15(10):2025–2039. https://doi.org/10.1111/j.1582-4934.2011.01374.x. (PMID: 10.1111/j.1582-4934.2011.01374.x217223024394214)
Ogata M, Hino SI, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. American Society for Microbiology 26(24):9220–9231. https://doi.org/10.1128/mcb.01453-06. (PMID: 10.1128/mcb.01453-06170306111698520)
Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. Nat Publ Group 415(6867):92–96. https://doi.org/10.1038/415092a. (PMID: 10.1038/415092a11780124)
Ye J, Rawson RB, Komuro R, Chen X, Davé UP, Prywes R, Brown MS, Goldstein JL (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. Cell Press 6(6):1355–1364. https://doi.org/10.1016/S1097-2765(00)00133-7. (PMID: 10.1016/S1097-2765(00)00133-7)
Thuerauf DJ, Morrison LE, Hoover H, Glembotski CC (2002) Coordination of ATF6-mediated transcription and ATF6 degradation by a domain that is shared with the viral transcription factor, VP16. J Biol Chem. American Society for Biochemistry and Molecular Biology 277(23):20734–20739. https://doi.org/10.1074/jbc.M201749200. (PMID: 10.1074/jbc.M20174920011909875)
Yoshida H, Haze K, Yanagi H, Yura T, Mori K (1998) Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose- regulated proteins: involvement of basic leucine zipper transcription factors. J Biol Chem. American Society for Biochemistry and Molecular Biology 273(50):33741–33749. https://doi.org/10.1074/jbc.273.50.33741. (PMID: 10.1074/jbc.273.50.337419837962)
Filiano JJ, Kinney HC (1994) A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model. Neonatology 65(3–4):194–197. https://doi.org/10.1159/000244052. (PMID: 10.1159/000244052)
Machaalani R, Waters KA (2014) Neurochemical abnormalities in the brainstem of the sudden infant death syndrome (SIDS). Paediatr Respir Rev. Elsevier Ltd 15(4):293–300. https://doi.org/10.1016/j.prrv.2014.09.008. (PMID: 10.1016/j.prrv.2014.09.00825304427)
Hotokezaka Y et al (2015) GSK-3β-dependent downregulation of γ-taxilin and αnAC merge to regulate ER stress responses. Cell Death Dis. Nature Publishing Group 6(4):e1719. https://doi.org/10.1038/cddis.2015.90. (PMID: 10.1038/cddis.2015.90258800864650556)
Shen Y, Yang J, Zhao J, Xiao C, Xu C, Xiang Y (2015) The switch from ER stress-induced apoptosis to autophagy via ROS-mediated JNK/p62 signals: a survival mechanism in methotrexate-resistant choriocarcinoma cells. Exp Cell Res. Academic Press Inc. 334(2):207–218. https://doi.org/10.1016/j.yexcr.2015.04.010. (PMID: 10.1016/j.yexcr.2015.04.01025912909)
Kang SJ et al (2017) Caspase-4 is essential for saikosaponin a-induced apoptosis acting upstream of caspase-2 and γ-H2AX in colon cancer cells. Oncotarget. Impact Journals LLC 8(59):100433–100448. https://doi.org/10.18632/oncotarget.22247. (PMID: 10.18632/oncotarget.22247292459905725032)
Sakabe I, Hu R, Jin L, Clarke R, Kasid UN (2015) TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of the unfolded protein response signaling. Breast Cancer Res Treat. Springer New York LLC 153(2):285–297. https://doi.org/10.1007/s10549-015-3536-7. (PMID: 10.1007/s10549-015-3536-7262686964559576)
Bettaieb A et al (2016) Anti-inflammatory actions of (−)-epicatechin in the adipose tissue of obese mice. Int J Biochem Cell Biol. Elsevier Ltd 81(Pt B):383–392. https://doi.org/10.1016/j.biocel.2016.08.044. (PMID: 10.1016/j.biocel.2016.08.044275924575514545)
Kim JY, Ko AR, Hyun HW, Min SJ, Kim JE (2017) PDI regulates seizure activity via NMDA receptor redox in rats. Sci Rep Nature Publishing Group 7. https://doi.org/10.1038/srep42491.
Tanimoto R et al (2009) Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3. Int J Cancer. John Wiley & Sons, Ltd 126(7):NA-NA. https://doi.org/10.1002/ijc.24764. (PMID: 10.1002/ijc.24764)
Kaslin J, Nystedt JM, Ostergård M, Peitsaro N, Panula P (2004) The orexin/hypocretin system in zebrafish is connected to the aminergic and cholinergic systems. J Neurosci. Soc Neurosci 24(11):2678–2689. https://doi.org/10.1523/JNEUROSCI.4908-03.2004. (PMID: 10.1523/JNEUROSCI.4908-03.2004150287606729510)
Tafuri S, Pavone LM, Mastellone V, Spina A, Avallone L, Vittoria A, Staiano N, Scala G (2009) Expression of orexin A and its receptor 1 in the choroid plexuses from buffalo brain. Neuropeptides. Churchill Livingstone 43(2):73–80. https://doi.org/10.1016/j.npep.2009.01.003. (PMID: 10.1016/j.npep.2009.01.00319250669)
Morawski M, Brückner G, Jäger C, Seeger G, Arendt T (2010) Neurons associated with aggrecan-based perineuronal nets are protected against tau pathology in subcortical regions in Alzheimer’s disease. Neuroscience. Pergamon 169(3):1347–1363. https://doi.org/10.1016/j.neuroscience.2010.05.022. (PMID: 10.1016/j.neuroscience.2010.05.02220497908)
Mai JK, Majtanik M and Paxinos G (2015) Atlas of the human brain.
Paxinos G and Huang XF (1995) Atlas of the human brainstem.
Scheper W, Hoozemans JJM (2015) The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol. Springer Berlin Heidelberg 130(3):315–331. https://doi.org/10.1007/s00401-015-1462-8. (PMID: 10.1007/s00401-015-1462-8262109904541706)
Stutzbach LD et al (2014) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun. BioMed central ltd. 2(1):31. https://doi.org/10.1186/2051-5960-1-31. (PMID: 10.1186/2051-5960-1-31)
Tan Z et al (2018) ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells. J Neuroinflammation 15(1):275. https://doi.org/10.1186/s12974-018-1311-5. (PMID: 10.1186/s12974-018-1311-5302415396151056)
Hosoi T et al (2019) Immobilization stress induces XBP1 splicing in the mouse brain. Biochem Biophys Res Commun. Elsevier B.V. 508(2):516–520. https://doi.org/10.1016/j.bbrc.2018.11.167. (PMID: 10.1016/j.bbrc.2018.11.16730509487)
Wang H, Wang X, Ke ZJ, Comer AL, Xu M, Frank JA, Zhang Z, Shi X et al (2015) Tunicamycin-induced unfolded protein response in the developing mouse brain. Toxicol Appl Pharmacol. Academic Press Inc 283(3):157–167. https://doi.org/10.1016/j.taap.2014.12.019. (PMID: 10.1016/j.taap.2014.12.019256200584361256)
Atkin JD, Farg MA, Walker AK, McLean C, Tomas D, Horne MK (2008) Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiology of Disease. Academic Press 30(3):400–407. https://doi.org/10.1016/J.NBD.2008.02.009. (PMID: 10.1016/J.NBD.2008.02.00918440237)
Murao N, Nishitoh H (2017) Role of the unfolded protein response in the development of central nervous system. J Biochem 162(3):155–162. https://doi.org/10.1093/jb/mvx047. (PMID: 10.1093/jb/mvx04728903548)
Naughton M, McMahon J, Healy S, FitzGerald U (2019) Profile of the unfolded protein response in rat cerebellar cortical development. J Comp Neurol. Wiley-Liss Inc 527(17):2910–2924. https://doi.org/10.1002/cne.24718. (PMID: 10.1002/cne.2471831132146)
Trobiani L, Favaloro FL, di Castro MA, di Mattia M, Cariello M, Miranda E, Canterini S, de Stefano ME et al (2018) UPR activation specifically modulates glutamate neurotransmission in the cerebellum of a mouse model of autism. Neurobiol Dis Academic Press Inc 120:139–150. https://doi.org/10.1016/j.nbd.2018.08.026. (PMID: 10.1016/j.nbd.2018.08.02630201312)
B’chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G et al (2013) The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. Oxford University Press 41(16):7683–7699. https://doi.org/10.1093/nar/gkt563. (PMID: 10.1093/nar/gkt563238047673763548)
Yang H et al (2020) ATF6 is a critical determinant of CHOP dynamics during the unfolded protein response. iScience. Elsevier Inc 23(2). https://doi.org/10.1016/j.isci.2020.100860.
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. Cell Press 107(7):881–891. https://doi.org/10.1016/S0092-8674(01)00611-0. (PMID: 10.1016/S0092-8674(01)00611-011779464)
Calton MA et al (2016) The cerebellum and SIDS: disordered breathing in a mouse model of developmental cerebellar Purkinje cell loss during recovery from hypercarbia. Front Neurol. Frontiers Research Foundation 7(MAY). https://doi.org/10.3389/fneur.2016.00078.
Cruz-Sánchez FF et al (1997) Cerebellar cortex delayed maturation in sudden infant death syndrome. J Neuropathol Exp Neurol. Lippincott Williams and Wilkins 56(4):340–346. https://doi.org/10.1097/00005072-199704000-00002. (PMID: 10.1097/00005072-199704000-000029100664)
Cooke JD, Larson B, Oscaesson O, Sjölund B (1971) Organization of afferent connections to cuneocerebellar tract. Exp Brain Res. Springer-Verlag 13(4):359–377. https://doi.org/10.1007/BF00234337. (PMID: 10.1007/BF002343375123643)
Sillitoe RV, Fu YH, Watson C (2012) Cerebellum. In: The Mouse Nervous System. Elsevier Inc., pp. 360–397. https://doi.org/10.1016/B978-0-12-369497-3.10011-1.
Paul MS and M Das J (2019) Neuroanatomy, superior and inferior olivary nucleus (superior and inferior Olivary complex), StatPearls. StatPearls Publishing. Available at: http://www.ncbi.nlm.nih.gov/pubmed/31194399 (Accessed: 15 Apr 2020).
Lapresle J, Hamida MB (1970) The dentato-olivary pathway: somatotopic relationship between the dentate nucleus and the contralateral inferior olive. Arch Neurol. American Medical Association 22(2):135–143. https://doi.org/10.1001/archneur.1970.00480200041004. (PMID: 10.1001/archneur.1970.004802000410044188259)
Machaalani R, Say M, Waters KA (2009) Serotoninergic receptor 1A in the sudden infant death syndrome brainstem medulla and associations with clinical risk factors. Acta Neuropathol 117:257–265. https://doi.org/10.1007/s00401-008-0468-x. (PMID: 10.1007/s00401-008-0468-x19052756)
Machaalani R, Waters KA (2003) NMDA receptor 1 expression in the brainstem of human infants and its relevance to the sudden infant death syndrome (SIDS). J Neuropathol Exp Neurol. Oxford Academic 62(10):1076–1085. https://doi.org/10.1093/JNEN/62.10.1076. (PMID: 10.1093/JNEN/62.10.107614575242)
Broadbelt KG, Paterson DS, Belliveau RA, Trachtenberg FL, Haas EA, Stanley C, Krous HF, Kinney HC (2011) Decreased GABAA receptor binding in the medullary serotonergic system in the sudden infant death syndrome. J Neuropathol Exp Neurol. Oxford Academic 70(9):799–810. https://doi.org/10.1097/NEN.0b013e31822c09bc. (PMID: 10.1097/NEN.0b013e31822c09bc218658883232677)
Fu J, Zhao L, Wang L, Zhu X (2015) Expression of markers of endoplasmic reticulum stress-induced apoptosis in the placenta of women with early and late onset severe pre-eclampsia. Taiwanese J Obstet Gynecol. Elsevier 54(1):19–23. https://doi.org/10.1016/J.TJOG.2014.11.002. (PMID: 10.1016/J.TJOG.2014.11.00225675914)
Machaalani R, Say M, Waters KA (2011) Effects of cigarette smoke exposure on nicotinic acetylcholine receptor subunits α7 and β2 in the sudden infant death syndrome (SIDS) brainstem. Toxicol Appl Pharmacol. Academic Press 257(3):396–404. https://doi.org/10.1016/j.taap.2011.09.023. (PMID: 10.1016/j.taap.2011.09.02322000980)
Machaalani R, Waters KA (2008) Neuronal cell death in the sudden infant death syndrome brainstem and associations with risk factors. Brain 131(1):218–228. https://doi.org/10.1093/brain/awm290. (PMID: 10.1093/brain/awm29018084013)
Waters KA, Meehan B, Huang JQ, Gravel RA, Michaud J, Côté A (1999) Neuronal apoptosis in sudden infant death syndrome. Pediatr Res. Lippincott Williams and Wilkins 45(2):166–172. https://doi.org/10.1203/00006450-199902000-00002. (PMID: 10.1203/00006450-199902000-0000210022585)
Nevárez N, De Lecea L (2018) Recent advances in understanding the roles of hypocretin/orexin in arousal, affect, and motivation. F1000Research. F1000 Research Ltd 7:1421. https://doi.org/10.12688/f1000research.15097.1. (PMID: 10.12688/f1000research.15097.1)
Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J et al (2012) Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature. Nat Publ Group 485(7399):507–511. https://doi.org/10.1038/nature11058. (PMID: 10.1038/nature11058226225793378208)
O’Connor T et al (2008) Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron. Cell Press 60(6):988–1009. https://doi.org/10.1016/j.neuron.2008.10.047. (PMID: 10.1016/j.neuron.2008.10.047191099072667382)
Srinivasan R, Richards CI, Xiao C, Rhee D, Pantoja R, Dougherty DA, Miwa JM, Lester HA (2012) Pharmacological chaperoning of nicotinic acetylcholine receptors reduces the endoplasmic reticulum stress response. Mol Pharmacol. American Society for Pharmacology and Experimental Therapeutics 81(6):759–769. https://doi.org/10.1124/mol.112.077792. (PMID: 10.1124/mol.112.077792223791213362896)
Srinivasan R et al (2016) Smoking-relevant nicotine concentration attenuates the unfolded protein response in dopaminergic neurons. https://doi.org/10.1523/JNEUROSCI.2126-15.2016.
Cai X-H, Li XC, Jin SW, Liang DS, Wen ZW, Cao HC, Mei HF, Wu Y et al (2014) Endoplasmic reticulum stress plays critical role in brain damage after chronic intermittent hypoxia in growing rats. Exp Neurol 257:148–156. https://doi.org/10.1016/j.expneurol.2014.04.029. (PMID: 10.1016/j.expneurol.2014.04.02924810321)
Carloni S et al (2014) Increased autophagy reduces endoplasmic reticulum stress after neonatal hypoxia-ischemia: Role of protein synthesis and autophagic pathways. https://doi.org/10.1016/j.expneurol.2014.03.002.
Chen D, Dixon BJ, Doycheva DM, Li B, Zhang Y, Hu Q, He Y, Guo Z et al (2018) IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic-ischemic brain injury in rats. J Neuroinflammation 15:32. https://doi.org/10.1186/s12974-018-1077-9. (PMID: 10.1186/s12974-018-1077-9293949345797348)
Doycheva D, Xu N, Kaur H, Malaguit J, McBride DW, Tang J, Zhang JH (2019) Adenoviral TMBIM6 vector attenuates ER-stress-induced apoptosis in a neonatal hypoxic-ischemic rat model. Dis Model Mech 12:dmm040352. https://doi.org/10.1242/dmm.040352. (PMID: 10.1242/dmm.040352316360866898997)
Lin Z et al (2017) ‘Intranasal basic fibroblast growth factor attenuates endoplasmic reticulum stress and brain injury in neonatal hypoxic-ischaemic injury’. Am J Transl Res. E-Century Publishing Corporation 9(2) 275–288. Available at: www.ajtr.org/ISSN:1943-8141/AJTR0041180 (Accessed: 22 Oct 2020).
Chan C-P, Siu KL, Chin KT, Yuen KY, Zheng B, Jin DY (2006) Modulation of the unfolded protein response by the severe acute respiratory syndrome coronavirus spike protein. J Virol 80(18):9279–9287. https://doi.org/10.1128/JVI.00659-06. (PMID: 10.1128/JVI.00659-06169405391563899)
Wang L, Cheng W, Zhang Z (2017) Respiratory syncytial virus infection accelerates lung fibrosis through the unfolded protein response in a bleomycin-induced pulmonary fibrosis animal model. Mol Med Rep Spandidos Publications 16(1):310–316. https://doi.org/10.3892/mmr.2017.6558. (PMID: 10.3892/mmr.2017.655828498407)
Waters KA and Tinworth KD (2001) Depression of ventilatory responses after daily, cyclic hypercapnic hypoxia in piglets. Available at: http://www.jap.org (Accessed: 7 May 2020).
Rea P (2014) Clinical anatomy of the cranial nerves. Clin Anatomy Cranial Nerves. Elsevier Inc. https://doi.org/10.1016/C2013-0-19192-1.
Bouret S, Sara SJ (2005) Network reset: A simplified overarching theory of locus coeruleus noradrenaline function. Trends Neurosci Elsevier Ltd 28(11):574–582. https://doi.org/10.1016/j.tins.2005.09.002. (PMID: 10.1016/j.tins.2005.09.00216165227)
Ambrose N, Waters KA, Rodriguez ML, Bailey K, Machaalani R (2018) Neuronal apoptosis in the brainstem medulla of sudden unexpected death in infancy (SUDI), and the importance of standardized SUDI classification. Forensic Sci Med Pathol. Humana Press Inc 14(1):42–56. https://doi.org/10.1007/s12024-018-9954-1. (PMID: 10.1007/s12024-018-9954-129460253)
Abrams JK et al (2004) Anatomic and functional topography of the dorsal raphe nucleus. In: Annals of the New York Academy of Sciences, vol 1018. New York, Academy of Sciences, pp. 46–57. https://doi.org/10.1196/annals.1296.005.
Yoshida H, Matsui T, Hosokawa N, Kaufman RJ, Nagata K, Mori K (2003) A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell. Cell Press 4(2):265–271. https://doi.org/10.1016/S1534-5807(03)00022-4. (PMID: 10.1016/S1534-5807(03)00022-412586069)
Zhao H et al (2011) Measuring the impact of cigarette smoke on the UPR. In: Methods in Enzymology. Academic Press Inc, pp. 147–164. https://doi.org/10.1016/B978-0-12-385116-1.00009-1.
Qie X et al (2017) Endoplasmic reticulum stress mediates methamphetamine-induced blood–brain barrier damage. Front Pharmacol. Frontiers media S.a. 8(SEP):639. https://doi.org/10.3389/fphar.2017.00639. (PMID: 10.3389/fphar.2017.00639289592035603670)
Cano M, Wang L, Wan J, Barnett BP, Ebrahimi K, Qian J, Handa JT (2014) Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells. Free Radic Biol Med. NIH Public Access 69:1–14. https://doi.org/10.1016/j.freeradbiomed.2014.01.004. (PMID: 10.1016/j.freeradbiomed.2014.01.004244341193960355)
Gdowski GT, McCrea RA (2000) Neck proprioceptive inputs to primate vestibular nucleus neurons. Exp Brain Res. Springer 135(4):511–526. https://doi.org/10.1007/s002210000542. (PMID: 10.1007/s00221000054211156315)

Keywords: ATF6; Arousal; Brainstem; ER stress; IRE1; PPERK

0 (Activating Transcription Factor 6)
0 (Orexins)
EC 2.7.11.1 (ERN1 protein, human)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 3.1.- (Endoribonucleases)

Date Created: 20210108 Date Completed: 20211118 Latest Revision: 20211204

20240829

10.1007/s12035-020-02244-2

33417217