title: A novel proteotoxic stress associated mechanism for macular corneal dystrophy.
abstract: Macular corneal dystrophy is a rare autosomal recessive eye disease affecting primarily the corneal stroma. Abnormal accumulation of proteoglycan aggregates has been observed intra- and extracellularly in the stromal layer. In addition to the stromal keratocytes and corneal lamellae, deposits are also present in the basal epithelial cells, endothelial cells and Descemet's membrane. Misfolding of proteins has a tendency to gather into aggregating deposits. We studied interaction of molecular chaperones and proteasomal clearance in macular dystrophy human samples and in human corneal HCE-2 epithelial cells. Seven cases of macular corneal dystrophy and four normal corneal buttons collected during corneal transplantation were examined for their expression patterns of heat shock protein 70, ubiquitin protein conjugates and SQSTM1/p62. In response to proteasome inhibition the same proteins were analyzed by western blotting. Slit-lamp examination, in vivo confocal cornea microscopy and transmission electron microscopy were used for morphological analyses. Heat shock protein 70, ubiquitin protein conjugates and SQSTM1/p62 were upregulated in both the basal corneal epithelial cells and the stromal keratocytes in macular corneal dystrophy samples that coincided with an increased expression of the same molecules under proteasome inhibition in the HCE-2 cells in vitro. We propose a novel regulatory mechanism that connects the molecular chaperone and proteasomal clearance system in the pathogenesis of macular corneal dystrophy.
authors.affiliation: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, and Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland. kai.kaarniranta@uef.fi.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.affiliation: Department of Ophthalmology, University of Debrecen, Medical Faculty, Debrecen, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Szalai
authors.affiliation: Ophthalmologic Clinic, District Railway Hospital, and Department of Physiology, Medical University of Silesia, Katowice, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Smedowski
authors.affiliation: Department of Anatomy, Histology and Embryology, University of Debrecen, Medical Faculty, Debrecen, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Hegyi
authors.affiliation: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Niko
authors.initials: N
authors.lastname: Kivinen
authors.affiliation: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Viiri
authors.affiliation: Ophthalmology Clinic, District Railway Hospital, Katowice, Poland.
authors.forename: Bogumil
authors.initials: B
authors.lastname: Wowra
authors.affiliation: Ophthalmology Clinic, District Railway Hospital, Katowice, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Dobrowolski
authors.affiliation: Department of Ophthalmology, University of Debrecen, Medical Faculty, Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Módis
authors.affiliation: Department of Ophthalmology, University of Debrecen, Medical Faculty, Debrecen, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Berta
authors.affiliation: Ophthalmology Clinic, District Railway Hospital, Katowice, Poland.
authors.forename: Edward
authors.initials: E
authors.lastname: Wylegala
authors.affiliation: Department of Anatomy, Histology and Embryology, University of Debrecen, Medical Faculty, Debrecen, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Felszeghy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003317:Corneal Dystrophies, Hereditary / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D011509:Proteoglycans; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex