{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T07:14:29Z","timestamp":1794035669702,"version":"4.8.0"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T00:00:00Z","timestamp":1615334400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T00:00:00Z","timestamp":1615334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870664"],"award-info":[{"award-number":["81870664"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81800838"],"award-info":[{"award-number":["81800838"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770946, 82070984"],"award-info":[{"award-number":["81770946, 82070984"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurodegeneration"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Oxidative stress is a common cause of neurodegeneration and plays a central role in retinal degenerative diseases. Heme oxygenase-1 (HMOX1) is a redox-regulated enzyme that is induced in neurodegenerative diseases and acts against oxidative stress but can also promote cell death, a phenomenon that is still unexplained in molecular terms. Here, we test whether HMOX1 has opposing effects during retinal degeneration and investigate the molecular mechanisms behind its pro-apoptotic role.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Basal and induced levels of HMOX1 in retinas are examined during light-induced retinal degeneration in mice. Light damage-independent HMOX1 induction at two different expression levels is achieved by intraocular injection of different doses of an adeno-associated virus vector expressing HMOX1. Activation of M\u00fcller glial cells, retinal morphology and photoreceptor cell death are examined using hematoxylin-eosin staining, TUNEL assays, immunostaining and retinal function are evaluated with electroretinograms. Downstream gene expression of HMOX1 is analyzed by RNA-seq, qPCR examination and western blotting. The role of one of these genes, the pro-apoptotic DNA damage inducible transcript\u00a03 (\n                      <jats:italic>Ddit3<\/jats:italic>\n                      ), is analyzed in a line of knockout mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Light-induced retinal degeneration leads to photoreceptor degeneration and concomitant HMOX1 induction. HMOX1 expression at low levels before light exposure prevents photoreceptor degeneration but expression at high levels directly induces photoreceptor degeneration even without light stress. Photoreceptor degeneration following high level expression of HMOX1 is associated with a mislocalization of rhodopsin in photoreceptors and an increase in the expression of DDIT3. Genetic deletion of\n                      <jats:italic>Ddit3<\/jats:italic>\n                      in knockout mice prevents photoreceptor cell degeneration normally resulting from high level HMOX1 expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The results reveal that the expression levels determine whether HMOX1 is protective or deleterious in the retina. Furthermore, in contrast to the protective low dose of HMOX1, the deleterious high dose is associated with induction of DDIT3 and endoplasmic reticulum stress as manifested, for instance, in rhodopsin mislocalization. Hence, future applications of\n                      <jats:italic>HMOX1<\/jats:italic>\n                      or its regulated targets in gene therapy approaches should carefully consider expression levels in order to avoid potentially devastating effects.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13024-021-00437-4","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T06:04:04Z","timestamp":1615356244000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3"],"prefix":"10.1186","volume":"16","author":[{"given":"Huirong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Lian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjin","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0705-8099","authenticated-orcid":false,"given":"Ling","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,10]]},"reference":[{"key":"437_CR1","doi-asserted-by":"publisher","first-page":"2556","DOI":"10.1021\/acs.accounts.5b00102","volume":"48","author":"C Ghosh","year":"2015","unstructured":"Ghosh C, Seal M, Mukherjee S, Ghosh Dey S. Alzheimer\u2019s disease: a Heme-Abeta perspective. Acc Chem Res. 2015;48:2556\u201364.","journal-title":"Acc Chem Res"},{"key":"437_CR2","doi-asserted-by":"publisher","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","volume":"3","author":"W Poewe","year":"2017","unstructured":"Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013.","journal-title":"Nat Rev Dis Primers"},{"key":"437_CR3","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","volume":"392","author":"P Mitchell","year":"2018","unstructured":"Mitchell P, Liew G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet. 2018;392:1147\u201359.","journal-title":"Lancet"},{"key":"437_CR4","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.preteyeres.2017.08.004","volume":"62","author":"PA Campochiaro","year":"2018","unstructured":"Campochiaro PA, Mir TA. The mechanism of cone cell death in Retinitis Pigmentosa. Prog Retin Eye Res. 2018;62:24\u201337.","journal-title":"Prog Retin Eye Res"},{"key":"437_CR5","doi-asserted-by":"crossref","unstructured":"Mendiola AS, Ryu JK, Bardehle S, Meyer-Franke A, Ang KK, Wilson C, Baeten KM, Hanspers K, Merlini M, Thomas S, et al. Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation. Nat Immunol. 2020;21:513\u201324.","DOI":"10.1038\/s41590-020-0654-0"},{"key":"437_CR6","doi-asserted-by":"publisher","first-page":"E4048","DOI":"10.1073\/pnas.1613067114","volume":"114","author":"S Nagar","year":"2017","unstructured":"Nagar S, Noveral SM, Trudler D, Lopez KM, McKercher SR, Han X, Yates JR 3rd, Pina-Crespo JC, Nakanishi N, Satoh T, et al. MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress. Proc Natl Acad Sci U S A. 2017;114:E4048\u201356.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"437_CR7","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1089\/ars.2013.5675","volume":"20","author":"LL Dunn","year":"2014","unstructured":"Dunn LL, Midwinter RG, Ni J, Hamid HA, Parish CR, Stocker R. New insights into intracellular locations and functions of heme oxygenase-1. Antioxid Redox Signal. 2014;20:1723\u201342.","journal-title":"Antioxid Redox Signal"},{"key":"437_CR8","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1152\/physrev.00003.2016","volume":"96","author":"A Ayer","year":"2016","unstructured":"Ayer A, Zarjou A, Agarwal A, Stocker R. Heme Oxygenases in cardiovascular health and disease. Physiol Rev. 2016;96:1449\u2013508.","journal-title":"Physiol Rev"},{"key":"437_CR9","doi-asserted-by":"publisher","first-page":"1940","DOI":"10.1161\/CIRCRESAHA.116.306588","volume":"118","author":"LE Otterbein","year":"2016","unstructured":"Otterbein LE, Foresti R, Motterlini R. Heme Oxygenase-1 and carbon monoxide in the heart: the balancing act between danger signaling and pro-survival. Circ Res. 2016;118:1940\u201359.","journal-title":"Circ Res"},{"key":"437_CR10","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1126\/science.3029864","volume":"235","author":"R Stocker","year":"1987","unstructured":"Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235:1043\u20136.","journal-title":"Science"},{"key":"437_CR11","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1089\/scd.2011.0304","volume":"21","author":"CY Lin","year":"2012","unstructured":"Lin CY, Peng CY, Huang TT, Wu ML, Lai YL, Peng DH, Chen PF, Chen HF, Yen BL, Wu KK, Yet SF. Exacerbation of oxidative stress-induced cell death and differentiation in induced pluripotent stem cells lacking heme oxygenase-1. Stem Cells Dev. 2012;21:1675\u201387.","journal-title":"Stem Cells Dev"},{"key":"437_CR12","doi-asserted-by":"publisher","first-page":"10925","DOI":"10.1073\/pnas.94.20.10925","volume":"94","author":"KD Poss","year":"1997","unstructured":"Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci U S A. 1997;94:10925\u201330.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"437_CR13","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1172\/JCI4165","volume":"103","author":"A Yachie","year":"1999","unstructured":"Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999;103:129\u201335.","journal-title":"J Clin Invest"},{"key":"437_CR14","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.nbd.2017.03.008","volume":"102","author":"J Chen-Roetling","year":"2017","unstructured":"Chen-Roetling J, Kamalapathy P, Cao Y, Song W, Schipper HM, Regan RF. Astrocyte heme oxygenase-1 reduces mortality and improves outcome after collagenase-induced intracerebral hemorrhage. Neurobiol Dis. 2017;102:140\u20136.","journal-title":"Neurobiol Dis"},{"key":"437_CR15","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.pneurobio.2018.06.008","volume":"172","author":"HM Schipper","year":"2019","unstructured":"Schipper HM, Song W, Tavitian A, Cressatti M. The sinister face of heme oxygenase-1 in brain aging and disease. Prog Neurobiol. 2019;172:40\u201370.","journal-title":"Prog Neurobiol"},{"key":"437_CR16","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.neurobiolaging.2005.01.016","volume":"27","author":"HM Schipper","year":"2006","unstructured":"Schipper HM, Bennett DA, Liberman A, Bienias JL, Schneider JA, Kelly J, Arvanitakis Z. Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiol Aging. 2006;27:252\u201361.","journal-title":"Neurobiol Aging"},{"key":"437_CR17","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1111\/j.1471-4159.2009.06160.x","volume":"110","author":"HM Schipper","year":"2009","unstructured":"Schipper HM, Song W, Zukor H, Hascalovici JR, Zeligman D. Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement. J Neurochem. 2009;110:469\u201385.","journal-title":"J Neurochem"},{"key":"437_CR18","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1111\/j.1471-4159.2009.06165.x","volume":"110","author":"W Song","year":"2009","unstructured":"Song W, Patel A, Qureshi HY, Han D, Schipper HM, Paudel HK. The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. J Neurochem. 2009;110:719\u201333.","journal-title":"J Neurochem"},{"key":"437_CR19","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.neurobiolaging.2017.06.017","volume":"58","author":"W Song","year":"2017","unstructured":"Song W, Cressatti M, Zukor H, Liberman A, Galindez C, Schipper HM. Parkinsonian features in aging GFAP.HMOX1 transgenic mice overexpressing human HO-1 in the astroglial compartment. Neurobiol Aging. 2017;58:163\u201379.","journal-title":"Neurobiol Aging"},{"key":"437_CR20","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1080\/15548627.2018.1476812","volume":"14","author":"N Meyer","year":"2018","unstructured":"Meyer N, Zielke S, Michaelis JB, Linder B, Warnsmann V, Rakel S, Osiewacz HD, Fulda S, Mittelbronn M, Munch C, et al. AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells. Autophagy. 2018;14:1693\u2013709.","journal-title":"Autophagy"},{"key":"437_CR21","doi-asserted-by":"publisher","first-page":"101469","DOI":"10.1016\/j.redox.2020.101469","volume":"34","author":"W Shu","year":"2020","unstructured":"Shu W, Baumann BH, Song Y, Liu Y, Wu X, Dunaief JL. Ferrous but not ferric iron sulfate kills photoreceptors and induces photoreceptor-dependent RPE autofluorescence. Redox Biol. 2020;34:101469.","journal-title":"Redox Biol"},{"key":"437_CR22","doi-asserted-by":"crossref","unstructured":"Gorbatyuk MS, Starr CR, Gorbatyuk OS. Endoplasmic reticulum stress: new insights into the pathogenesis and treatment of retinal degenerative diseases. Prog Retin Eye Res. 2020;79:100860.","DOI":"10.1016\/j.preteyeres.2020.100860"},{"key":"437_CR23","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1254312","volume":"345","author":"M Lu","year":"2014","unstructured":"Lu M, Lawrence DA, Marsters S, Acosta-Alvear D, Kimmig P, Mendez AS, Paton AW, Paton JC, Walter P, Ashkenazi A. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science. 2014;345:98\u2013101.","journal-title":"Science"},{"key":"437_CR24","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/j.cmet.2009.03.003","volume":"9","author":"E Thorp","year":"2009","unstructured":"Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe\u2212\/\u2212 and Ldlr\u2212\/\u2212 mice lacking CHOP. Cell Metab. 2009;9:474\u201381.","journal-title":"Cell Metab"},{"key":"437_CR25","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13024-018-0250-z","volume":"13","author":"T McLaughlin","year":"2018","unstructured":"McLaughlin T, Falkowski M, Park JW, Keegan S, Elliott M, Wang JJ, Zhang SX. Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration. Mol Neurodegener. 2018;13:16.","journal-title":"Mol Neurodegener"},{"key":"437_CR26","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.redox.2013.07.004","volume":"2","author":"S Bansal","year":"2014","unstructured":"Bansal S, Biswas G, Avadhani NG. Mitochondria-targeted heme oxygenase-1 induces oxidative stress and mitochondrial dysfunction in macrophages, kidney fibroblasts and in chronic alcohol hepatotoxicity. Redox Biol. 2014;2:273\u201383.","journal-title":"Redox Biol"},{"key":"437_CR27","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1002\/jcp.20509","volume":"206","author":"W Song","year":"2006","unstructured":"Song W, Su H, Song S, Paudel HK, Schipper HM. Over-expression of heme oxygenase-1 promotes oxidative mitochondrial damage in rat astroglia. J Cell Physiol. 2006;206:655\u201363.","journal-title":"J Cell Physiol"},{"key":"437_CR28","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1111\/j.1471-4159.2009.06007.x","volume":"109","author":"H Zukor","year":"2009","unstructured":"Zukor H, Song W, Liberman A, Mui J, Vali H, Fillebeen C, Pantopoulos K, Wu TD, Guerquin-Kern JL, Schipper HM. HO-1-mediated macroautophagy: a mechanism for unregulated iron deposition in aging and degenerating neural tissues. J Neurochem. 2009;109:776\u201391.","journal-title":"J Neurochem"},{"key":"437_CR29","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1074\/jbc.M410413200","volume":"280","author":"XM Liu","year":"2005","unstructured":"Liu XM, Peyton KJ, Ensenat D, Wang H, Schafer AI, Alam J, Durante W. Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle. Role in cell survival. J Biol Chem. 2005;280:872\u20137.","journal-title":"J Biol Chem"},{"key":"437_CR30","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51698","volume":"9","author":"H Li","year":"2020","unstructured":"Li H, Lian L, Liu B, Chen Y, Yang J, Jian S, Zhou J, Xu Y, Ma X, Qu J, Hou L. KIT ligand protects against both light-induced and genetic photoreceptor degeneration. Elife. 2020;9:e51698.","journal-title":"Elife"},{"key":"437_CR31","doi-asserted-by":"publisher","first-page":"5699","DOI":"10.1167\/iovs.07-0340","volume":"48","author":"MH Sun","year":"2007","unstructured":"Sun MH, Pang JH, Chen SL, Kuo PC, Chen KJ, Kao LY, Wu JY, Lin KK, Tsao YP. Photoreceptor protection against light damage by AAV-mediated overexpression of heme oxygenase-1. Invest Ophthalmol Vis Sci. 2007;48:5699\u2013707.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"437_CR32","doi-asserted-by":"publisher","first-page":"14806","DOI":"10.1073\/pnas.1404140111","volume":"111","author":"C He","year":"2014","unstructured":"He C, Zhao C, Kumar A, Lee C, Chen M, Huang L, Wang J, Ren X, Jiang Y, Chen W, et al. Vasoprotective effect of PDGF-CC mediated by HMOX1 rescues retinal degeneration. Proc Natl Acad Sci U S A. 2014;111:14806\u201311.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"437_CR33","doi-asserted-by":"publisher","first-page":"7272","DOI":"10.1038\/s41598-017-07683-x","volume":"7","author":"H Li","year":"2017","unstructured":"Li H, Fan L, Zhu S, Shin MK, Lu F, Qu J, Hou L. Epilation induces hair and skin pigmentation through an EDN3\/EDNRB-dependent regenerative response of melanocyte stem cells. Sci Rep. 2017;7:7272.","journal-title":"Sci Rep"},{"key":"437_CR34","doi-asserted-by":"publisher","first-page":"101789","DOI":"10.1016\/j.redox.2020.101789","volume":"38","author":"C Fern\u00e1ndez-Mend\u00edvil","year":"2021","unstructured":"Fern\u00e1ndez-Mend\u00edvil C, Luengo E, Trigo-Alonso P, Garc\u00eda-Magro N, Negredo P, L\u00f3pez MG. Protective role of microglial HO-1 blockade in aging: implication of iron metabolism. Redox Biol. 2021;38:101789.","journal-title":"Redox Biol"},{"key":"437_CR35","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1038\/s41418-019-0371-0","volume":"27","author":"Z Li","year":"2020","unstructured":"Li Z, Li H, Xu X, Wang L, Liu B, Zheng W, Lian L, Song Y, Xia X, Hou L, et al. Haploinsufficiency of GCP4 induces autophagy and leads to photoreceptor degeneration due to defective spindle assembly in retina. Cell Death Differ. 2020;27:556\u201372.","journal-title":"Cell Death Differ"},{"key":"437_CR36","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/ng984","volume":"32","author":"W Hao","year":"2002","unstructured":"Hao W, Wenzel A, Obin MS, Chen CK, Brill E, Krasnoperova NV, Eversole-Cire P, Kleyner Y, Taylor A, Simon MI, et al. Evidence for two apoptotic pathways in light-induced retinal degeneration. Nat Genet. 2002;32:254\u201360.","journal-title":"Nat Genet"},{"key":"437_CR37","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1073\/pnas.92.4.1177","volume":"92","author":"RK Kutty","year":"1995","unstructured":"Kutty RK, Kutty G, Wiggert B, Chader GJ, Darrow RM, Organisciak DT. Induction of heme oxygenase 1 in the retina by intense visible light: suppression by the antioxidant dimethylthiourea. Proc Natl Acad Sci U S A. 1995;92:1177\u201381.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"437_CR38","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.preteyeres.2004.08.002","volume":"24","author":"A Wenzel","year":"2005","unstructured":"Wenzel A, Grimm C, Samardzija M, Reme CE. Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog Retin Eye Res. 2005;24:275\u2013306.","journal-title":"Prog Retin Eye Res"},{"key":"437_CR39","doi-asserted-by":"publisher","first-page":"5785","DOI":"10.1073\/pnas.1821000116","volume":"116","author":"W Xiong","year":"2019","unstructured":"Xiong W, Wu DM, Xue Y, Wang SK, Chung MJ, Ji X, Rana P, Zhao SR, Mai S, Cepko CL. AAV cis-regulatory sequences are correlated with ocular toxicity. Proc Natl Acad Sci U S A. 2019;116:5785\u201394.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"437_CR40","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1089\/hum.2018.144","volume":"29","author":"H Khabou","year":"2018","unstructured":"Khabou H, Cordeau C, Pacot L, Fisson S, Dalkara D. Dosage thresholds and influence of transgene cassette in adeno-associated virus-related toxicity. Hum Gene Ther. 2018;29:1235\u201341.","journal-title":"Hum Gene Ther"},{"key":"437_CR41","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/bs.pmbts.2015.02.007","volume":"132","author":"I Nemet","year":"2015","unstructured":"Nemet I, Ropelewski P, Imanishi Y. Rhodopsin trafficking and mistrafficking: signals, molecular components, and mechanisms. Prog Mol Biol Transl Sci. 2015;132:39\u201371.","journal-title":"Prog Mol Biol Transl Sci"},{"key":"437_CR42","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1111\/jnc.12116","volume":"125","author":"T Nakanishi","year":"2013","unstructured":"Nakanishi T, Shimazawa M, Sugitani S, Kudo T, Imai S, Inokuchi Y, Tsuruma K, Hara H. Role of endoplasmic reticulum stress in light-induced photoreceptor degeneration in mice. J Neurochem. 2013;125:111\u201324.","journal-title":"J Neurochem"},{"key":"437_CR43","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.biocel.2018.06.005","volume":"102","author":"DG Lee","year":"2018","unstructured":"Lee DG, Kam MK, Kim KM, Kim HS, Kwon OS, Lee HS, Lee DS. Peroxiredoxin 5 prevents iron overload-induced neuronal death by inhibiting mitochondrial fragmentation and endoplasmic reticulum stress in mouse hippocampal HT-22 cells. Int J Biochem Cell Biol. 2018;102:10\u20139.","journal-title":"Int J Biochem Cell Biol"},{"key":"437_CR44","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/sj.cdd.4401817","volume":"13","author":"M Boyce","year":"2006","unstructured":"Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 2006;13:363\u201373.","journal-title":"Cell Death Differ"},{"key":"437_CR45","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/1750-1326-9-35","volume":"9","author":"J Dunys","year":"2014","unstructured":"Dunys J, Duplan E, Checler F. The transcription factor X-box binding protein-1 in neurodegenerative diseases. Mol Neurodegener. 2014;9:35.","journal-title":"Mol Neurodegener"},{"key":"437_CR46","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/nature14656","volume":"523","author":"Y Kang","year":"2015","unstructured":"Kang Y, Zhou XE, Gao X, He Y, Liu W, Ishchenko A, Barty A, White TA, Yefanov O, Han GW, et al. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature. 2015;523:561\u20137.","journal-title":"Nature"},{"key":"437_CR47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.preteyeres.2017.10.002","volume":"62","author":"D Athanasiou","year":"2018","unstructured":"Athanasiou D, Aguila M, Bellingham J, Li W, McCulley C, Reeves PJ, Cheetham ME. The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. Prog Retin Eye Res. 2018;62:1\u201323.","journal-title":"Prog Retin Eye Res"},{"key":"437_CR48","doi-asserted-by":"publisher","first-page":"7590","DOI":"10.1167\/iovs.12-10221","volume":"53","author":"H Kroeger","year":"2012","unstructured":"Kroeger H, Messah C, Ahern K, Gee J, Joseph V, Matthes MT, Yasumura D, Gorbatyuk MS, Chiang WC, LaVail MM, Lin JH. Induction of endoplasmic reticulum stress genes, BiP and chop, in genetic and environmental models of retinal degeneration. Invest Ophthalmol Vis Sci. 2012;53:7590\u20139.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"437_CR49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063205","volume":"8","author":"S Nashine","year":"2013","unstructured":"Nashine S, Bhootada Y, Lewin AS, Gorbatyuk M. Ablation of C\/EBP homologous protein does not protect T17M RHO mice from retinal degeneration. PLoS One. 2013;8:e63205.","journal-title":"PLoS One"}],"container-title":["Molecular Neurodegeneration"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-021-00437-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13024-021-00437-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-021-00437-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T08:13:58Z","timestamp":1615364038000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularneurodegeneration.biomedcentral.com\/articles\/10.1186\/s13024-021-00437-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,10]]},"references-count":49,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["437"],"URL":"https:\/\/doi.org\/10.1186\/s13024-021-00437-4","relation":{},"ISSN":["1750-1326"],"issn-type":[{"value":"1750-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,10]]},"assertion":[{"value":"16 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal experiments were carried out in accordance with the approved guidelines of the Wenzhou Medical University Institutional Animal Care and Use Committee (Permit Number: WZMCOPT-090316).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16"}}