title: Walking the tightrope: proteostasis and neurodegenerative disease.
abstract: A characteristic of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), is the aggregation of specific proteins into protein inclusions and/or plaques in degenerating brains. While much of the aggregated protein consists of disease specific proteins, such as amyloid-β, α-synuclein, or superoxide dismutase1 (SOD1), many other proteins are known to aggregate in these disorders. Although the role of protein aggregates in the pathogenesis of neurodegenerative diseases remains unknown, the ubiquitous association of misfolded and aggregated proteins indicates that significant dysfunction in protein homeostasis (proteostasis) occurs in these diseases. Proteostasis is the concept that the integrity of the proteome is in fine balance and requires proteins in a specific conformation, concentration, and location to be functional. In this review, we discuss the role of specific mechanisms, both inside and outside cells, which maintain proteostasis, including molecular chaperones, protein degradation pathways, and the active formation of inclusions, in neurodegenerative diseases associated with protein aggregation. A characteristic of many neurodegenerative diseases is the aggregation of specific proteins, which alone provides strong evidence that protein homeostasis is disrupted in these disease states. Proteostasis is the maintenance of the proteome in the correct conformation, concentration, and location by functional pathways such as molecular chaperones and protein degradation machinery. Here, we discuss the potential roles of quality control pathways, both inside and outside cells, in the loss of proteostasis during aging and disease.
authors.affiliation: Proteostasis and Disease Research Centre, School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.|Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Yerbury
authors.affiliation: Proteostasis and Disease Research Centre, School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.|Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
authors.forename: Lezanne
authors.initials: L
authors.lastname: Ooi
authors.affiliation: Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, The University of California, California, USA.|Howard Hughes Medical Institute, The University of California, Berkeley, California, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia.|The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Darren N
authors.initials: DN
authors.lastname: Saunders
authors.affiliation: Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Danny M
authors.initials: DM
authors.lastname: Hatters
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Beart
authors.affiliation: Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Cashman
authors.affiliation: Proteostasis and Disease Research Centre, School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.|Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wilson
authors.affiliation: Proteostasis and Disease Research Centre, School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.|Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
authors.forename: Heath
authors.initials: H
authors.lastname: Ecroyd
mesh_terms: D000818:Animals; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D060066:Protein Interaction Maps / Q000502:physiology; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000378:metabolism* / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D025801:Ubiquitin
keywords: aggregation; aging; autophagy; chaperones; heat-shock proteins; ubiquitin-proteasome system