Abstract
Age-related macular degeneration (AMD) is a complex neurodegenerative disease resulting in a loss of central vision in the elderly. It is currently assumed that impairment of autophagy may be one of the key mechanisms leading to AMD. Here we estimated the influence of age-related autophagy alterations in the retina on the development of AMD-like retinopathy in senescence-accelerated OXYS rats. Significant changes in the expression of the autophagy proteins were absent at the age preceding the development of retinopathy (age 20 days). We found increased levels of LC3A/B, Atg7, and Atg12–Atg5 conjugated proteins in the OXYS retina during manifestation of this retinopathy at the age of 3 months. By contrast, in the retina of 18-month-old OXYS rats with a progressive stage of retinopathy, we revealed significantly decreased protein levels of Atg7 and Atg12–Atg5 as compared to age-matched Wistar rats. Simultaneously with perturbation of the autophagic response, the necrosome subunits Ripk1 and Ripk3 were detected in the OXYS retina. The downregulation of autophagy markers coincided with amyloid β accumulation (Moab-2) in the retinal pigment epithelium and choroid. Using high-throughput RNA sequencing, we found a missense single-nucleotide polymorphism (SNP) in the Pik3c2b gene associated with autophagy regulation. This SNP was predicted to significantly affect protein structure. Our data prove participation of the autophagic pathway in the progression of AMD-like retinopathy.
Similar content being viewed by others
References
Alliouachene S, Bilanges B, Chicanne G, Anderson KE, Pearce W, Ali K, Scudamore CL (2015) Inactivation of the class II PI3K-C2β potentiates insulin signaling and sensitivity. Cell Rep 13(9):1881–1894. https://doi.org/10.1016/j.celrep.2015.10.052
Besirli CG, Chinskey ND, Zheng QD, Zacks DN (2011) Autophagy activation in the injured photoreceptor inhibits fas-mediated apoptosis. Invest Ophthalmol Vis Sci 52(7):4193–4199. https://doi.org/10.1167/iovs.10-7090
Boya P, Esteban-Martínez L, Serrano-Puebla A et al (2016) Autophagy in the eye: development, degeneration, and aging. Prog Retin Eye Res 55:206–245. https://doi.org/10.1016/j.preteyeres.2016.08.001
Devereaux K, Dall’Armi C, Alcazar-Roman A, Ogasawara Y, Zhou X, Wang F et al (2013) Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PLoS ONE 8(10):e76405. https://doi.org/10.1371/journal.pone.0076405
Dvoriantchikova G, Degterev A, Ivanov D (2014) Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia–reperfusion-induced retinal damage. Exp Eye Res 123:1–7. https://doi.org/10.1016/j.exer.2014.04.009
Ferrington DA, Sinha D, Kaarniranta K (2016) Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration. Prog Retin Eye Res 51:69–89. https://doi.org/10.1016/j.preteyeres.2015.09.002
Golestaneh N, Chu Y, Xiao YY, Stoleru GL, Theos AC (2017) Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration. Cell Death Dis 8(1):e2537. https://doi.org/10.1038/cddis.2016.453
Hanus J, Zhang H, Wang Z, Liu Q, Zhou Q, Wang S (2013) Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells. Cell Death Dis 4(12):e965. https://doi.org/10.1038/cddis.2013.478
Jankauskas SS, Pevzner IB, Andrianova NV, Zorova LD, Popkov VA, Silachev DN et al (2017) The age-associated loss of ischemic preconditioning in the kidney is accompanied by mitochondrial dysfunction, increased protein acetylation and decreased autophagy. Sci Rep 7:44430. https://doi.org/10.1038/srep44430
Kaarniranta K, Sinha D, Blasiak J, Kauppinen A, Veréb Z, Salminen A et al (2013) Autophagy and heterophagy dysregulation leads to retinal pigment epithelium dysfunction and development of age-related macular degeneration. Autophagy 9(7):973–984. https://doi.org/10.4161/auto.24546
Kaarniranta K, Tokarz P, Koskela A, Paterno J, Blasiak J (2017) Autophagy regulates death of retinal pigment epithelium cells in age-related macular degeneration. Cell Biol Toxicol 33(2):113–128. https://doi.org/10.1007/s10565-016-9371-8
Kolosova NG, Stefanova NA, Korbolina EE et al (2014) Senescence-accelerated OXYS rats: a genetic model of premature aging and age-related diseases. Adv Gerontol 4:294. https://doi.org/10.1134/S2079057014040146
Korbolina EE, Zhdankina AA, Fursova AZ et al (2016) Genes of susceptibility to early neurodegenerative changes in the rat retina and brain: analysis by means of congenic strains. BMC Genet 17(Suppl 3):153. https://doi.org/10.1186/s12863-016-0461-7
Kozhevnikova OS, Korbolina EE, Ershov NI, Kolosova NG (2013a) Rat retinal transcriptome: effects of aging and AMD-like retinopathy. Cell Cycle 12(11):1745–1761. https://doi.org/10.4161/cc.24825
Kozhevnikova OS, Korbolina EE, Stefanova NA et al (2013b) Association of AMD-like retinopathy development with an Alzheimer’s disease metabolic pathway in OXYS rats. Biogerontology 14(6):753–762. https://doi.org/10.1007/s10522-013-9439-2
Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY (2012) Age-related macular degeneration. Lancet 379(9827):1728–1738. https://doi.org/10.1016/S0140-6736(12)60282-7
Markaki M, Tavernarakis N (2011) The role of autophagy in genetic pathways influencing ageing. Biogerontology 12(5):377–386. https://doi.org/10.1007/s10522-011-9324-9
Mitter SK, Song C, Qi X, Mao H et al (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10(11):1989–2005. https://doi.org/10.4161/auto.36184
Morel E, Chamoun Z, Lasiecka ZM, Chan RB, Williamson RL, Vetanovetz C et al (2013) PI3P regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun 4:2250. https://doi.org/10.1038/ncomms3250
Muraleva NA, Kozhevnikova OS, Zhdankina AA et al (2014) The mitochondria-targeted antioxidant SkQ1 restores αB-crystallin expression and protects against AMD-like retinopathy in OXYS rats. Cell Cycle 13(22):3499–3505. https://doi.org/10.4161/15384101.2014.958393
Nilsson P, Loganathan K, Sekiguchi M, Matsuba Y, Hui K, Tsubuki S et al (2013) Aβ secretion and plaque formation depend on autophagy. Cell Rep 5(1):61–69. https://doi.org/10.1016/j.celrep.2013.08.042
Perusek L, Sahu B, Parmar T, Maeno H, Arai E, Le YZ et al (2015) A2E Accumulation and the Maintenance of the Visual Cycle are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium. J Biol Chem 290(48):29035–29044. https://doi.org/10.1074/jbc.M115.682310
Rodríguez-Muela N, Koga H, García-Ledo L, de la Villa P, de la Rosa EJ, Cuervo AM, Boya P (2013) Balance between autophagic pathways preserves retinal homeostasis. Aging Cell 12(3):478–488. https://doi.org/10.1111/acel.12072
Shen HM, Codogno P (2012) Autophagy is a survival force via suppression of necrotic cell death. Exp Cell Res 318(11):1304–1308. https://doi.org/10.1016/j.yexcr.2012.02.006
Stefanova NA, Kozhevnikova OS, Vitovtov AO et al (2014) Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease. Cell Cycle 13(6):898–909. https://doi.org/10.4161/cc.28255
Telegina DV, Korbolina EE, Ershov NI, Kolosova NG, Kozhevnikova OS (2015) Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy. Cell Cycle 14(22):3544–3556. https://doi.org/10.1080/15384101.2015.1080399
Telegina DV, Kozhevnikova OS, Bayborodin SI, Kolosova NG (2017a) Contributions of age-related alterations of the retinal pigment epithelium and of glia to the AMD-like pathology in OXYS rats. Sci Rep 7:41533. https://doi.org/10.1038/srep41533
Telegina DV, Kozhevnikova OS, Kolosova NG (2017b) Molecular mechanisms of cell death in retina during development of age-related macular degeneration. Adv Gerontol 7:17. https://doi.org/10.1134/S2079057017010155
Trichonas G, Murakami Y, Thanos A et al (2010) Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis. Proc Natl Acad Sci USA 107(50):21695–21700. https://doi.org/10.1073/pnas.1009179107
Unal Cevik I, Dalkara T (2003) Intravenously administered propidium iodide labels necrotic cells in the intact mouse brain after injury. Cell Death Differ 10(8):928–929. https://doi.org/10.1038/sj.cdd.4401250
Wei T, Kang Q, Ma B, Gao S, Li X, Liu Y (2015) Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats. Exp Ther Med 9(2):476–482. https://doi.org/10.3892/etm.2014.2084
Xie J, Zhu R, Peng Y, Gao W, Du J, Zhao L et al (2017) Tumor necrosis factor-alpha regulates photoreceptor cell autophagy after retinal detachment. Sci Rep 7(1):17108. https://doi.org/10.1038/s41598-017-17400-3
Yao J, Jia L, Khan N, Lin C, Mitter SK, Boulton ME, Dunaief JL, Klionsky DJ, Guan J-L, Thompson DA, Zacks DN (2015) Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium. Autophagy 11(6):939–953. https://doi.org/10.1080/15548627.2015.1041699
You Z, Savitz SI, Yang J, Degterev A, Yuan J, Cuny GD et al (2008) Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab 28(9):1564–1573. https://doi.org/10.1038/jcbfm.2008.44
Youmans KL, Tai LM, Kanekiyo T et al (2012) Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody. Mol Neurodegener 7:8. https://doi.org/10.1186/1750-1326-7-8
Zhang J, Bai Y, Huang L, Qi Y et al (2015) Protective effect of autophagy on human retinal pigment epithelial cells against lipofuscin fluorophore A2E: implications for age-related macular degeneration. Cell Death Dis 12(6):e1972. https://doi.org/10.1038/cddis.2015.330
Acknowledgements
Microscopy was performed at the Microscopy Center of the Institute of Cytology and Genetics, SB RAS, Russia. This work was supported by a Russian Scientific Foundation Grant (16-15-10005).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Kozhevnikova, O.S., Telegina, D.V., Devyatkin, V.A. et al. Involvement of the autophagic pathway in the progression of AMD-like retinopathy in senescence-accelerated OXYS rats. Biogerontology 19, 223–235 (2018). https://doi.org/10.1007/s10522-018-9751-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-018-9751-y