title: Clearance of misfolded and aggregated proteins by aggrephagy and implications for aggregation diseases.
abstract: Processing of misfolded proteins is important in order for the cell to maintain its normal functioning and homeostasis. Three systems control the quality of proteins: chaperone-mediated refolding, proteasomal degradation of ubiquitinated proteins, and finally, when the two others fail, aggrephagy, as selective form of autophagy, degrades ubiquitin-labelled aggregated cargos. In this route misfolded proteins gradually form larger aggregates, aggresomes and they eventually become double membrane-wrapped organelles called autophagosomes, which become degraded when they fuse to lysosomes, for reuse by the cell. The stages, the main molecules participating in the process, and the regulation of aggrephagy are discussed here, as is the role of protein aggregation in protein accumulation diseases. In particular, we emphasize that both Alzheimer's disease and age-related macular degeneration, two of the most common pathologies in the aged, are characterized by altered protein clearance and deposits. Based on the hypothesis that manipulations of autophagy may be potentially useful in these and other aggregation-related diseases, we will discuss some promising therapeutic strategies to counteract protein aggregates-induced cellular toxicity.
authors: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. Electronic address: Juha.Hyttinen@uef.fi.
authors: Juha M T
authors: JM
authors: Hyttinen
authors: Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy.
authors: Marialaura
authors: M
authors: Amadio
authors: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors: Johanna
authors: J
authors: Viiri
authors: Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy.
authors: Alessia
authors: A
authors: Pascale
authors: Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors: Antero
authors: A
authors: Salminen
authors: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
authors: Kai
authors: K
authors: Kaarniranta
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D018832:Molecular Chaperones / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D017510:Protein Folding; D021381:Protein Transport; D057165:Proteostasis Deficiencies / Q000378:metabolism* / Q000473:pathology; D057149:Ubiquitinated Proteins / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018832:Molecular Chaperones; D066329:Protein Aggregates; D057149:Ubiquitinated Proteins; D046988:Proteasome Endopeptidase Complex
keywords: Age-related macular degeneration; Aggrephagy; Aggresome; Alzheimer's disease; Autophagy; Protein folding