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Eszter Szalai, Kai Kaarniranta, Laszlo Modis Jr., Andras Berta, Adrian Smedowski, Johanna Viiri, Bogumil Wowra, Dariusz Dobrowolski, Edward Wylegala, Szabolcs Felszeghy; Role of proteasomal proteolysis in the pathogenesis of macular corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1018.
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© ARVO (1962-2015); The Authors (2016-present)
Macular corneal dystrophy (MIM #217800), an autosomal recessive disorder primarily affecting the corneal stroma, is characterized by abnormal accumulation of glycosaminoglycans. Our goal was to analyse the expression level of protein aggregation regulatory molecules in human macular dystrophy corneas and in cultured human corneal epithelial cells (HCE-2) under proteasomal inhibition in vitro.
Four cases of macular dystrophy and 4 normal human corneal buttons collected during corneal transplantation were examined for their expression patterns of Heat shock protein 70 (Hsp70), SQSTM1/p62 and ubiquitin protein conjugates by fluorescent immunohistochemistry. Expression levels in response to different concentrations of proteasomal inhibitor treatment (MG-132) were also analysed in HCE-2 cells by western blotting and transmission electron microscopy.
In macular dystrophy samples, strongly upregulated Hsp70, SQSTM1/p62 and ubiquitin protein conjugates were observed in basal epithelial cells. Weak Hsp70 labelling, moderate ubiquitin and SQSTM1/p62 positivity were present in stromal keratocytes in macular dystrophy. All the studied proteins were also highly elevated under proteasomal inhibition in HCE-2 cells in vitro.
This study first demonstrates the upregulation of Hsp70, SQSTM1/p62 and ubiquitin protein conjugates in the basal epithelial cells and stromal keratocytes in macular dystrophy. Our data may support the role of impaired ubiquitin/proteasomal protein degradation and abnormal protein homeostasis in the pathogenesis of macular corneal dystrophy.
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