Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis

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• 作者：Niko Kivinen ; Szabolcs Felszeghy ; Aino I. Kinnunen ; Niko Setälä…
• 刊名：Biogerontology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：17
• 期：4
• 页码：749-761
• 全文大小：4,186 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Cell Biology
  Geriatrics and Gerontology
  Developmental Biology
  
• 出版者：Springer Netherlands
• ISSN：1573-6768
• 卷排序：17

文摘

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−/−p> 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−/−p> 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.KeywordsAgingAutophagyCollagen XVIIIMaculaRetinaAnimal model