title: Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract.
abstract: Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington's 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.
authors.affiliation: Department of Biology, Stanford University, Stanford, United States.|Department of Genetics, Stanford University, Stanford, United States.
authors.forename: Koning
authors.identifier: 0000-0003-2607-449X
authors.initials: K
authors.lastname: Shen
authors.affiliation: Center for Drug Discovery, Department of Neurobiology, Duke University Medical Center, Durham, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Calamini
authors.affiliation: Department of Biology, Stanford University, Stanford, United States.|Department of Genetics, Stanford University, Stanford, United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fauerbach
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Boxue
authors.initials: B
authors.lastname: Ma
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Shahmoradian
authors.affiliation: Department of Biology, Stanford University, Stanford, United States.|Department of Genetics, Stanford University, Stanford, United States.
authors.forename: Ivana L
authors.initials: IL
authors.lastname: Serrano Lachapel
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
authors.affiliation: Center for Drug Discovery, Department of Neurobiology, Duke University Medical Center, Durham, United States.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
authors.affiliation: Department of Biology, Stanford University, Stanford, United States.|Department of Genetics, Stanford University, Stanford, United States.
authors.forename: Judith
authors.identifier: 0000-0003-2302-6943
authors.initials: J
authors.lastname: Frydman
mesh_terms: D000818:Animals; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology*; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000633:toxicity*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000633:toxicity*; D010455:Peptides; D011487:Protein Conformation; D055503:Protein Multimerization; D051381:Rats
chemical_list: C499524:Htt protein, rat; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine
keywords: Huntington's disease; aggregation; biochemistry; cell biology; human; mouse; proteostasis