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The role of autophagy in age‐related macular degeneration
Author(s) -
Kivinen Niko
Publication year - 2018
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/aos.13753
Subject(s) - macular degeneration , choroidal neovascularization , retinal pigment epithelium , degeneration (medical) , medicine , autophagy , blindness , ophthalmology , retina , neovascularization , retinal , disease , optometry , pathology , biology , neuroscience , angiogenesis , genetics , apoptosis
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed countries. The prevalence of disease is expected to triple in the approaching decades. At the moment, only those cases which present choroidal neovascularization, a hallmark of wet AMD, are treatable with antiproliferative therapeutic agents. Unfortunately, these cases account for only 10–15% of all AMD patients, i.e. most patients are still without any treatment options. The key role in the development of AMD can be traced the degeneration of retinal pigment epithelium cells (RPE) which are the caretakers of photoreceptor rod and cones. The aim of the study was to clarify the role of autophagy in the pathogenesis of AMD. Ocular samples from knock-out mice and human cadavers were used in the experiments in conjunction with laboratory grown RPE-cell lines; samples were examined by modern cell and molecular biological techniques as well as immunohistochemical methods. Finally, a test series with collagen 18 total knock-out (Col18a1 / ) mice was conducted. The above methods were used to evaluate proteostasis of RPE in the mouse model. The levels of SQSTM1/p62 protein were elevated in macular areas of AMD cadaver samples; this was interpreted as evidence that a dysfunction of autophagy is involved in AMD pathogenesis. We also noted that the molecular chaperone, Hsp70, which has a strong cytoprotective capacity, evades autophagic clearance. The current standard-of-care for AMD has no effect on the activity of autophagy in RPE cells. An age-related insufficiency of proteostasis was observed together with RPE degeneration in Col18a1 / mice. We conclude that SQSTM1/p62 is a good marker for impaired autophagy. Furthermore, Hsp70 upregulation could be used as a therapeutic target against retinal pigment epithelium (RPE) degeneration and in the development novel treatments for AMD. Finally, Col18a1 / mice, which display AMD-like tissue alterations may represent a relevant animal model for impaired autophagy and AMD. National Library of Medicine Classification: WW 270, QU 375, QZ 140 Medical Subject Headings: Age-related Macular Degeneration; AMD pathophysiology; Autophagy; Animal model; Mouse model; Ocular disease; Blindness; Visual impairment Kivinen Niko Autophagian rooli silm€anpohjan ik€arappeumassa, tutkimuksia AMD:n patogeneesist€a It€a-Suomen yliopisto, terveystieteiden tiedekunta Publications of the University of Eastern Finland. Dissertations in Health Sciences Numero 400. 2017. 117 s. ISBN (print): 978-952-61-2413-1 ISBN (pdf): 978-952-61-2414-8 ISSN (print): 1798-5706 ISSN (pdf): 1798-5714 ISSN-L: 1798-5706