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In Huntington\u2019s disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases.<\/jats:p>","DOI":"10.7554\/elife.18065","type":"journal-article","created":{"date-parts":[[2016,10,18]],"date-time":"2016-10-18T08:00:11Z","timestamp":1476777611000},"source":"Crossref","is-referenced-by-count":85,"title":["Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract"],"prefix":"10.7554","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2607-449X","authenticated-orcid":true,"given":"Koning","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, United States"},{"name":"Department of Genetics, Stanford University, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Calamini","sequence":"additional","affiliation":[{"name":"Center for Drug 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L","family":"Serrano Lachapel","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, United States"},{"name":"Department of Genetics, Stanford University, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wah","family":"Chiu","sequence":"additional","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald C","family":"Lo","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery, Department of Neurobiology, Duke University Medical Center, Durham, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2302-6943","authenticated-orcid":true,"given":"Judith","family":"Frydman","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, 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