title: Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis.
abstract: Collagen XVIII has the structural properties of both collagen and proteoglycan. It has been found at the basement membrane/stromal interface where it is thought to mediate their attachment. Endostatin, a proteolytic fragment from collagen XVIII C-terminal end has been reported to possess anti-angiogenic properties. Age-related vision loss in collagen XVIII mutant mice has been accompanied with a pathological accumulation of deposits under the retinal pigment epithelium (RPE). We have recently demonstrated that impaired proteasomal and autophagy clearance are associated with the pathogenesis of age-related macular degeneration. This study examined the staining levels of proteasomal and autophagy markers in the RPE of different ages of the Col18a1 (-/-) mice. Eyes from 3, 6-7, 10-13 and 18 months old mice were enucleated and embedded in paraffin according to the routine protocol. Sequential 5 μm-thick parasagittal samples were immunostained for proteasome and autophagy markers ubiquitin (ub), SQSTM1/p62 and beclin-1. The levels of immunopositivity in the RPE cells were evaluated by confocal microscopy. Collagen XVIII knock-out mice had undergone age-related RPE degeneration accompanied by an accumulation of drusen-like deposits. Ub protein conjugate staining was prominent in both RPE cytoplasm and extracellular space whereas SQSTM1/p62 and beclin-1 stainings were clearly present in the basal part of RPE cell cytoplasm in the Col18a1 (-/-) mice. SQSTM1/p62 displayed mild extracellular space staining. Disturbed proteostasis regulated by collagen XVIII might be responsible for the RPE degeneration, increased protein aggregation, ultimately leading to choroidal neovascularization.
authors.affiliation: Department of Ophthalmology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland. niko.kivinen@uef.fi.
authors.forename: Niko
authors.initials: N
authors.lastname: Kivinen
authors.affiliation: Department of Anatomy, Histology and Embryology, Dental Faculty, University of Debrecen, Debrecen, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Felszeghy
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.|Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
authors.forename: Aino I
authors.initials: AI
authors.lastname: Kinnunen
authors.affiliation: Jyväskylä Central Hospital, Jyväskylä, Finland.
authors.forename: Niko
authors.initials: N
authors.lastname: Setälä
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Aikio
authors.affiliation: Department of Ophthalmology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Kinnunen
authors.affiliation: Pathology and Forensic Medicine and Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland and Imaging Center, Clinical Pathology, Institute of Clinical Medicine, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Reijo
authors.initials: R
authors.lastname: Sironen
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Kauppinen
authors.affiliation: Department of Ophthalmology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D005260:Female; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057165:Proteostasis Deficiencies / Q000378:metabolism* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology
chemical_list: C520294:collagen XXVIII, mouse; D003094:Collagen
keywords: Aging; Animal model; Autophagy; Collagen XVIII; Macula; Retina