title: Proteostasis impairment in protein-misfolding and -aggregation diseases.
abstract: Cells possess an extensive network of components to safeguard proteome integrity and maintain protein homeostasis (proteostasis). When this proteostasis network (PN) declines in performance, as may be the case during aging, newly synthesized proteins are no longer able to fold efficiently and metastable proteins lose their functionally active conformations, particularly under conditions of cell stress. Apart from loss-of-function effects, a critical consequence of PN deficiency is the accumulation of cytotoxic protein aggregates, which are also associated with many age-dependent neurodegenerative diseases and other medical disorders. Here we discuss recent evidence that the chronic production of aberrantly folded and aggregated proteins in these diseases is harmful by overtaxing PN capacity, setting in motion a vicious cycle of increasing proteome imbalance that eventually leads to PN collapse and cell death.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hipp
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Sae-Hun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. Electronic address: uhartl@biochem.mpg.de.
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Hartl
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D017510:Protein Folding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000235:genetics* / Q000473:pathology
chemical_list: D018832:Molecular Chaperones; D011506:Proteins
keywords: degradation; molecular chaperones; neurodegenerative disease; protein (mis)folding; protein aggregation; proteostasis