title: A model in which heat shock protein 90 targets protein-folding clefts: rationale for a new approach to neuroprotective treatment of protein folding diseases.
abstract: In an EBM Minireview published in 2010, we proposed that the heat shock protein (Hsp)90/Hsp70-based chaperone machinery played a major role in determining the selection of proteins that have undergone oxidative or other toxic damage for ubiquitination and proteasomal degradation. The proposal was based on a model in which the Hsp90 chaperone machinery regulates signaling by modulating ligand-binding clefts. The model provides a framework for thinking about the development of neuroprotective therapies for protein-folding diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and the polyglutamine expansion disorders, such as Huntington's disease (HD) and spinal and bulbar muscular atrophy (SBMA). Major aberrant proteins that misfold and accumulate in these diseases are "client" proteins of the abundant and ubiquitous stress chaperone Hsp90. These Hsp90 client proteins include tau (AD), α-synuclein (PD), huntingtin (HD), and the expanded glutamine androgen receptor (polyQ AR) (SBMA). In this Minireview, we update our model in which Hsp90 acts on protein-folding clefts and show how it forms a rational basis for developing drugs that promote the targeted elimination of these aberrant proteins.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Pratt
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morishima
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California 94158, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA osawa@umich.edu.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Osawa
mesh_terms: D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D017510:Protein Folding; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000628:therapy*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D017981:Receptors, Neurotransmitter; D051844:alpha-Synuclein; C069474:glutamine receptor; D016875:tau Proteins
keywords: Proteostasis; carboxyl-terminus of Hsc70-interacting protein; heat shock protein 70; heat shock protein 90; neurodegeneration; ubiquitination