{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T22:46:07Z","timestamp":1770417967352,"version":"3.49.0"},"reference-count":39,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2019,9,27]],"date-time":"2019-09-27T00:00:00Z","timestamp":1569542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["18-75-00031"],"award-info":[{"award-number":["18-75-00031"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Age-related macular degeneration (AMD) is one of the main causes of vision impairment in the elderly. Autophagy is the process of delivery of cytoplasmic components into lysosomes for cleavage; its age-related malfunction may contribute to AMD. Here we showed that the development of AMD-like retinopathy in OXYS rats is accompanied by retinal transcriptome changes affecting genes involved in autophagy. These genes are associated with kinase activity, immune processes, and FoxO, mTOR, PI3K-AKT, MAPK, AMPK, and neurotrophin pathways at preclinical and manifestation stages, as well as vesicle transport and processes in lysosomes at the progression stage. We demonstrated a reduced response to autophagy modulation (inhibition or induction) in the OXYS retina at age 16 months: expression of genes Atg5, Atg7, Becn1, Nbr1, Map1lc3b, p62, and Gabarapl1 differed between OXYS and Wistar (control) rats. The impaired reactivity of autophagy was confirmed by a decreased number of autophagosomes under the conditions of blocked autophagosome\u2013lysosomal fusion according to immunohistochemical analysis and transmission electron microscopy. Thus, the development of AMD signs occurs against the background of changes in the expression of autophagy-related genes and a decrease in autophagy reactivity: the ability to enhance autophagic flux in response to stress.<\/jats:p>","DOI":"10.3390\/ijms20194804","type":"journal-article","created":{"date-parts":[[2019,9,27]],"date-time":"2019-09-27T11:14:35Z","timestamp":1569582875000},"page":"4804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Disruptions of Autophagy in the Rat Retina with Age During the Development of Age-Related-Macular-Degeneration-like Retinopathy"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6475-4061","authenticated-orcid":false,"given":"Oyuna S.","family":"Kozhevnikova","sequence":"first","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (SB RAS), Pr. Lavrentyeva 10, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8096-0519","authenticated-orcid":false,"given":"Darya V.","family":"Telegina","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (SB RAS), Pr. Lavrentyeva 10, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikhail A.","family":"Tyumentsev","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (SB RAS), Pr. Lavrentyeva 10, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-8544","authenticated-orcid":false,"given":"Nataliya G.","family":"Kolosova","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (SB RAS), Pr. Lavrentyeva 10, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.biocel.2013.04.013","article-title":"Cellular and molecular mechanisms of age-related macular degeneration: From impaired autophagy to neovascularization","volume":"45","author":"Klettner","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5293258","DOI":"10.1155\/2017\/5293258","article-title":"Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role?","volume":"2017","author":"Blasiak","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Blasiak, J., Pawlowska, E., Szczepanska, J., and Kaarniranta, K. (2019). Interplay between Autophagy and the Ubiquitin-Proteasome System and Its Role in the Pathogenesis of Age-Related Macular Degeneration. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010210"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s10565-016-9371-8","article-title":"Autophagy regulates death of retinal pigment epithelium cells in age-related macular degeneration","volume":"33","author":"Kaarniranta","year":"2017","journal-title":"Cell Biol. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.4161\/auto.36184","article-title":"Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD","volume":"10","author":"Mitter","year":"2014","journal-title":"Autophagy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1080\/15548627.2015.1041699","article-title":"Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium","volume":"11","author":"Yao","year":"2015","journal-title":"Autophagy"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1080\/15548627.2018.1474314","article-title":"Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion","volume":"14","author":"Mauthe","year":"2018","journal-title":"Autophagy"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"790","DOI":"10.3389\/fendo.2018.00790","article-title":"Hallmarks of Aging: An Autophagic Perspective","volume":"9","author":"Barbosa","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Ren, S., Liu, Y., Gao, K., Liu, Z., and Zhang, Z. (2017). Inhibition of Starvation-Triggered Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in ARPE-19 Cells by Taurine through Modulating the Expression of Calpain-1 and Calpain-2. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102146"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nrd3802","article-title":"Autophagy modulation as a potential therapeutic target for diverse diseases","volume":"11","author":"Rubinsztein","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.cell.2013.06.012","article-title":"Noncanonical autophagy promotes the visual cycle","volume":"154","author":"Kim","year":"2013","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1126\/scisignal.aag3315","article-title":"Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium","volume":"11","author":"Yu","year":"2018","journal-title":"Sci. Signal"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1134\/S2079057014040146","article-title":"Senescence-accelerated OXYS rats: A genetic model of premature aging and age-related diseases","volume":"4","author":"Kolosova","year":"2014","journal-title":"Adv. Gerontol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41533","DOI":"10.1038\/srep41533","article-title":"Contributions of age-related alterations of the retinal pigment epithelium and of glia to the AMD-like pathology in OXYS rats","volume":"7","author":"Telegina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s10522-018-9751-y","article-title":"Involvement of the autophagic pathway in the progression of AMD-like retinopathy in senescence-accelerated OXYS rats","volume":"19","author":"Kozhevnikova","year":"2018","journal-title":"Biogerontology"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Muraleva, N.A., Kozhevnikova, O.S., Fursova, A.Z., and Kolosova, N.G. (2019). Suppression of AMD-Like Pathology by Mitochondria-Targeted Antioxidant SkQ1 Is Associated with a Decrease in the Accumulation of Amyloid \u03b2 and in mTOR Activity. Antioxidants, 8.","DOI":"10.3390\/antiox8060177"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1007\/s10522-013-9439-2","article-title":"Association of AMD-like retinopathy development with an Alzheimer\u2019s disease metabolic pathway in OXYS rats","volume":"14","author":"Kozhevnikova","year":"2013","journal-title":"Biogerontology"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Telegina, D.V., Kolosova, N.G., and Kozhevnikova, O.S. (2019). Immunohistochemical localization of NGF, BDNF, and their receptors in a normal and AMD-like rat retina. BMC Med. Genom., 12.","DOI":"10.1186\/s12920-019-0493-8"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"49","DOI":"10.18632\/aging.100427","article-title":"Quantitative trait loci on chromosome 1 for cataract and AMD-like retinopathy in senescence-accelerated OXYS rats","volume":"4","author":"Korbolina","year":"2012","journal-title":"Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.18632\/aging.101537","article-title":"p62\/SQSTM1 coding plasmid prevents age related macular degeneration in a rat model","volume":"10","author":"Kolosova","year":"2018","journal-title":"Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.4161\/cc.24825","article-title":"Rat retinal transcriptome: Effects of aging and AMD-like retinopathy","volume":"12","author":"Kozhevnikova","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3544","DOI":"10.1080\/15384101.2015.1080399","article-title":"Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy","volume":"14","author":"Telegina","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12749","DOI":"10.1073\/pnas.1705572114","article-title":"SNARE priming is essential for maturation of autophagosomes but not for their formation","volume":"114","author":"Abada","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1080\/21541248.2017.1317699","article-title":"Roles for RAB24 in autophagy and disease","volume":"9","author":"Eskelinen","year":"2018","journal-title":"Small GTPases"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Keeling, E., Lotery, A.J., Tumbarello, D.A., and Ratnayaka, J.A. (2018). Impaired Cargo Clearance in the Retinal Pigment Epithelium (RPE) Underlies Irreversible Blinding Diseases. Cells, 7.","DOI":"10.20944\/preprints201801.0269.v1"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"19687","DOI":"10.1074\/jbc.M112.350934","article-title":"Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress","volume":"287","author":"Liu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_29","first-page":"3632169","article-title":"Autophagy Dysfunction, Cellular Senescence, and Abnormal Immune-Inflammatory Responses in AMD: From Mechanisms to Therapeutic Potential","volume":"2019","author":"Wang","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.bbrc.2018.01.159","article-title":"Autophagy activated by SIRT6 regulates A\u03b2 induced inflammatory response in RPEs","volume":"496","author":"Feng","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","first-page":"228","article-title":"Early AMD-like defects in the RPE and retinal degeneration in aged mice with RPE-specific deletion of Atg5 or Atg7","volume":"23","author":"Zhang","year":"2017","journal-title":"Mol. Vis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lei, L., Tzekov, R., Li, H., McDowell, J.H., Gao, G., Smith, W.C., Tang, S., and Kaushal, S. (2017). Inhibition or Stimulation of Autophagy Affects Early Formation of Lipofuscin-Like Autofluorescence in the Retinal Pigment Epithelium Cell. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040728"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/s41419-018-1044-5","article-title":"Rapamycin and fasting sustain autophagy response activated by ischemia\/reperfusion injury and promote retinal ganglion cell survival","volume":"9","author":"Russo","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ymeth.2015.01.008","article-title":"Autophagic flux determination in vivo and ex vivo","volume":"75","author":"Boya","year":"2015","journal-title":"Methods"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.exer.2015.08.018","article-title":"Lysosomes: Regulators of autophagy in the retinal pigmented epithelium","volume":"144","author":"Sinha","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.redox.2018.09.011","article-title":"Loss of NRF-2 and PGC-1\u03b1 genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration","volume":"20","author":"Felszeghy","year":"2019","journal-title":"Redox Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"44430","DOI":"10.1038\/srep44430","article-title":"The age-associated loss of ischemic preconditioning in the kidney is accompanied by mitochondrial dysfunction, increased protein acetylation and decreased autophagy","volume":"7","author":"Jankauskas","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Korbolina, E.E., Zhdankina, A.A., Fursova, A.Z., Kozhevnikova, O.S., and Kolosova, N.G. (2016). Genes of susceptibility to early neurodegenerative changes in the rat retina and brain: Analysis by means of congenic strains. BMC Genet., 17.","DOI":"10.1186\/s12863-016-0461-7"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Fedoseeva, L.A., Klimov, L.O., Ershov, N.I., Efimov, V.M., Markel, A.L., Orlov, Y.L., and Redina, O.E. (2019). The differences in brain stem transcriptional profiling in hypertensive ISIAH and normotensive WAG rats. BMC Genom., 20.","DOI":"10.1186\/s12864-019-5540-5"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4804\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:25:02Z","timestamp":1760189102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4804"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,27]]},"references-count":39,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20194804"],"URL":"https:\/\/doi.org\/10.3390\/ijms20194804","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,27]]}}}