title: Preventing α-synuclein aggregation: the role of the small heat-shock molecular chaperone proteins.
abstract: Protein homeostasis, or proteostasis, is the process of maintaining the conformational and functional integrity of the proteome. The failure of proteostasis can result in the accumulation of non-native proteins leading to their aggregation and deposition in cells and in tissues. The amyloid fibrillar aggregation of the protein α-synuclein into Lewy bodies and Lewy neuritis is associated with neurodegenerative diseases classified as α-synucleinopathies, which include Parkinson's disease and dementia with Lewy bodies. The small heat-shock proteins (sHsps) are molecular chaperones that are one of the cell's first lines of defence against protein aggregation. They act to stabilise partially folded protein intermediates, in an ATP-independent manner, to maintain cellular proteostasis under stress conditions. Thus, the sHsps appear ideally suited to protect against α-synuclein aggregation, yet these fail to do so in the context of the α-synucleinopathies. This review discusses how sHsps interact with α-synuclein to prevent its aggregation and, in doing so, highlights the multi-faceted nature of the mechanisms used by sHsps to prevent the fibrillar aggregation of proteins. It also examines what factors may contribute to α-synuclein escaping the sHsp chaperones in the context of the α-synucleinopathies.
authors: School of Biological Sciences and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, 2522, Australia.
authors: Dezerae
authors: D
authors: Cox
authors: Research School of Chemistry, The Australian National University, Canberra, Australian Capital Territory, 0200, Australia.
authors: John A
authors: JA
authors: Carver
authors: School of Biological Sciences and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, 2522, Australia. Electronic address: heathe@uow.edu.au.
authors: Heath
authors: H
authors: Ecroyd
mesh_terms: D000818:Animals; D050888:Heat-Shock Proteins, Small / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D050888:Heat-Shock Proteins, Small; D018832:Molecular Chaperones; D051844:alpha-Synuclein
keywords: Amyloid; Parkinson's disease; Protein aggregation; Proteostasis; α-Synuclein; αB-crystallin