title: Heat shock proteins as gatekeepers of proteolytic pathways-Implications for age-related macular degeneration (AMD).
abstract: Age-related macular degeneration (AMD) is the major diagnosis for severe and irreversible central loss of vision in elderly people in the developed countries. The loss of vision involves primarily a progressive degeneration and cell death of postmitotic retinal pigment epithelial cells (RPE), which secondarily evokes adverse effects on photoreceptor cells. The RPE cells are exposed to chronic oxidative stress from three sources: their high levels of oxygen consumption, their exposure to the high levels of lipid peroxidation derived from the photoreceptor outer segments and their exposure to constant light stimuli. Cells increase the expression of heat shock proteins (HSPs) in order to normalize their growth conditions in response to various environmental stress factors, e.g. oxidative stress. The HSPs function as molecular chaperones by preventing the accumulation of cellular cytotoxic protein aggregates and assisting in correct folding of both nascent and misfolded proteins. Increased HSPs levels are observed in the retina of AMD patients, evidence of stressed tissue. A hallmark of RPE cell aging is lysosomal lipofuscin accumulation reflecting a weakened capacity to degrade proteins in lysosomes. The presence of lipofuscin increases the misfolding of intracellular proteins, which evokes additional stress in the RPE cells. If the capacity of HSPs to repair protein damages is overwhelmed, then the proteins are mainly cleared in proteasomes or in lysosomes. In this review, we discuss the role of heat shock proteins, proteasomes, and lysosomes and autophagic processes in RPE cell proteolysis and how these might be involved in development of AMD. In addition to classical lysosomal proteolysis, we focus on the increasing evidence that, HSPs, proteasomes and autophagy regulate protein turnover in the RPE cells and thus have important roles in AMD disease.
authors.affiliation: Department of Ophthalmology, Kuopio University Hospital and University of Kuopio, Kuopio, Finland. kaarnira@messi.uku.fi
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.forename: Eeva-Liisa
authors.initials: EL
authors.lastname: Eskelinen
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kopitz
mesh_terms: D000818:Animals; D001343:Autophagy; D003600:Cytosol / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008062:Lipofuscin / Q000096:biosynthesis; D008247:Lysosomes / Q000378:metabolism*; D008268:Macular Degeneration / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D006360:Heat-Shock Proteins; D008062:Lipofuscin; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex