title: The neurodegenerative-disease-related protein sacsin is a molecular chaperone.
abstract: Various human neurodegenerative disorders are associated with processes that involve misfolding of polypeptide chains. These so-called protein misfolding disorders include Alzheimer's and Parkinson's diseases and an increasing number of inherited syndromes that affect neurons involved in motor control circuits throughout the central nervous system. The reasons behind the particular susceptibility of neurons to misfolded proteins are currently not known. The main function of a class of proteins known as molecular chaperones is to prevent protein misfolding and aggregation. Although neuronal cells contain the major known classes of molecular chaperones, central-nervous-system-specific chaperones that maintain the neuronal proteome free from misfolded proteins are not well defined. In this study, we assign a novel molecular chaperone activity to the protein sacsin responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay, a degenerative disorder of the cerebellum and spinal cord. Using purified components, we demonstrate that a region of sacsin that contains a segment with homology to the molecular chaperone Hsp90 is able to enhance the refolding efficiency of the model client protein firefly luciferase. We show that this region of sacsin is highly capable of maintaining client polypeptides in soluble folding-competent states. Furthermore, we demonstrate that sacsin can efficiently cooperate with members of the Hsp70 chaperone family to increase the yields of correctly folded client proteins. Thus, we have identified a novel chaperone directly involved in a human neurodegenerative disorder.
authors: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0620, USA.
authors: John F
authors: JF
authors: Anderson
authors: Efrain
authors: E
authors: Siller
authors: José M
authors: JM
authors: Barral
mesh_terms: D000818:Animals; D029968:Escherichia coli Proteins / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones; D019636:Neurodegenerative Diseases; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: C494635:DnaJ protein, E coli; D029968:Escherichia coli Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; C498616:Sacs protein, mouse; D008156:Luciferases; C063842:dnaK protein, E coli