title: The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis.
abstract: A truncated form of the Huntington's disease (HD) protein that contains the polyglutamine repeat, Httex1p, causes HD-like phenotypes in multiple model organisms. Molecular signatures of pathogenesis appear to involve distinct domains within this polypeptide. We studied the contribution of each domain, singly or in combination, to sub-cellular localization, aggregation and intracellular Ca2+ ([Ca2+]i) dynamics in cells. We demonstrate that sub-cellular localization is most strongly influenced by the first 17 amino acids, with this sequence critically controlling Httex1p mitochondrial localization and also promoting association with the endoplasmic reticulum (ER) and Golgi. This domain also enhances the formation of visible aggregates and together with the expanded polyQ repeat acutely disrupts [Ca2+]i levels in glutamate-challenged PC12 cells. Isolated cortical mitochondria incubated with Httex1p resulted in uncoupling and depolarization of these organelles, further supporting the idea that Httex1p-dependent mitochondrial dysfunction could be instrumental in promoting acute Ca2+ dyshomeostasis. Interestingly, neither mitochondrial nor ER associations seem to be required to promote long-term [Ca2+]i dyshomeostasis.
authors.affiliation: Department of Psychiatry and Human Behavior, University of California, Gillespie 2121, Irvine, CA 92697, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Rockabrand
authors.forename: Natalia
authors.initials: N
authors.lastname: Slepko
authors.forename: Antonello
authors.initials: A
authors.lastname: Pantalone
authors.forename: Vidya N
authors.initials: VN
authors.lastname: Nukala
authors.forename: Aleksey
authors.initials: A
authors.lastname: Kazantsev
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.forename: Joan S
authors.initials: JS
authors.lastname: Steffan
authors.forename: Stefano L
authors.initials: SL
authors.lastname: Sensi
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002525:Cerebellar Cortex / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006706:Homeostasis; D000071058:Huntingtin Protein; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics; D011392:Proline / Q000737:chemistry; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D045222:Electron Transport Chain Complex Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D017382:Reactive Oxygen Species; C097188:polyglutamine; D011392:Proline; D002118:Calcium