title: A compact beta model of huntingtin toxicity.
abstract: Huntington disease results from an expanded polyglutamine region in the N terminus of the huntingtin protein. HD pathology is characterized by neuronal degeneration and protein inclusions containing N-terminal fragments of mutant huntingtin. Structural information is minimal, though it is believed that mutant huntingtin polyglutamine adopts β structure upon conversion to a toxic form. To this end, we designed mammalian cell expression constructs encoding compact β variants of Htt exon 1 N-terminal fragment and tested their ability to aggregate and induce toxicity in cultured neuronal cells. In parallel, we performed molecular dynamics simulations, which indicate that constructs with expanded polyglutamine β-strands are stabilized by main-chain hydrogen bonding. Finally, we found a correlation between the reactivity to 3B5H10, an expanded polyglutamine antibody that recognizes a compact β rich hairpin structure, and the ability to induce cell toxicity. These data are consistent with an important role for a compact β structure in mutant huntingtin-induced cell toxicity.
authors.affiliation: From the Division of Neurobiology, Department of Psychiatry, Children's Medical Surgical Center.
authors.forename: Qi Charles
authors.initials: QC
authors.lastname: Zhang
authors.affiliation: the Department of Biochemistry and Biophysics, and.
authors.forename: Tzu-Lan
authors.initials: TL
authors.lastname: Yeh
authors.affiliation: the Department of Biochemistry and Biophysics, and.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Leyva
authors.affiliation: From the Division of Neurobiology, Department of Psychiatry, Children's Medical Surgical Center.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Frank
authors.affiliation: the Chemistry and Chemical Biology Graduate Program,; Medical Scientist Training Program,; Gladstone Institute of Neurological Disease, and.
authors.forename: Jason
authors.initials: J
authors.lastname: Miller
authors.affiliation: the Departments of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90089.
authors.forename: Yujin E
authors.initials: YE
authors.lastname: Kim
authors.affiliation: the Departments of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90089.
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
authors.affiliation: Gladstone Institute of Neurological Disease, and; the Departments of Neurology and Physiology, University of California, San Francisco, California 94158, and.
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.affiliation: the Department of Biochemistry and Biophysics, and.
authors.forename: Mario L
authors.initials: ML
authors.lastname: Amzel
authors.affiliation: From the Division of Neurobiology, Department of Psychiatry, Children's Medical Surgical Center,; the Departments of Neuroscience and Neurology, Johns Hopkins University School of Medicine, Baltimore, Mayland 21287.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: From the Division of Neurobiology, Department of Psychiatry, Children's Medical Surgical Center,. Electronic address: mpoirie1@jhmi.edu.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Poirier
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D000071058:Huntingtin Protein; D006860:Hydrogen Bonding; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins