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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\u2019s disease (AD), Parkinson\u2019s disease (PD), and the polyglutamine expansion disorders, such as Huntington\u2019s disease (HD) and spinal and bulbar muscular atrophy (SBMA). Major aberrant proteins that misfold and accumulate in these diseases are \u201cclient\u201d proteins of the abundant and ubiquitous stress chaperone Hsp90. These Hsp90 client proteins include tau (AD), \u03b1-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.<\/jats:p>","DOI":"10.1177\/1535370214539444","type":"journal-article","created":{"date-parts":[[2014,7,2]],"date-time":"2014-07-02T23:29:35Z","timestamp":1404343775000},"page":"1405-1413","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":24,"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"],"prefix":"10.3389","volume":"239","author":[{"given":"William B","family":"Pratt","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, 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