Lack of collagen XVIII in mice evokes age-dependent deficiency in retinal pigment epithelium proteostasis

Purpose Collagen XVIII is a unique component of basement membranes (BMs) with the structural properties of both a collagen and a proteoglycan. It has been found at the basement membrane/stromal interface and is thought to mediate their attachment. Proteolytic cleavage within its C-terminal domain releases a fragment, endostatin, which has been reported to have anti-angiogenesis effects. Age-dependent loss of vision in the collagen XVIII mutant mice is associated with pathological accumulation of deposits under the retinal pigment epithelium. We have recently shown that impaired proteasomal and autophagy clearance associate with the pathogenesis of age-related macular degeneration (AMD). In this study, staining levels of proteasomal and autophagy markers were studied in different ages of the Col18a1−/− mice. Methods Enucleated eyes from 3, 12 and 18 months old mice were embedded in paraffin according to a routine protocol. Serial 5 μm-thick parasagittal samples were immunostained for proteasomal ubiquitin (Ub) and autophagy markers SQSTM1/p62 and Beclin. The extent of immunopositivity in the retinal pigment epithelial cells was evaluated during confocal microscopic analysis. Results Lack of collagen XVIII in mice evoked age-dependent retinal pigment epithelium (RPE) degeneration and drusen-like deposit accumulation. Proteasomal Ub protein conjugate staining was prominent in both RPE cytoplasm and extracellular space. Autophagy markers SQSTM1/p62 and beclin stainings were prominent in the basal part of RPE cell cytoplasm in the Col18a1−/− mice. Conclusions Disturbed proteostasis regulated by collagen XVIII may induce RPE degeneration, increase protein aggregation and finally predispose to the choroidal neovascularization.