title: Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice.
abstract: Huntington's disease (HD) is caused by an expanded N-terminal glutamine tract that endows huntingtin with a striatal-selective structural property ultimately toxic to medium spiny neurons. In precise genetic models of juvenile HD, HdhQ92 and HdhQ111 knock-in mice, long polyglutamine segments change huntingtin's physical properties, producing HD-like in vivo correlates in the striatum, including nuclear localization of a version of the full-length protein predominant in medium spiny neurons, and subsequent formation of N-terminal inclusions and insoluble aggregate. These changes show glutamine length dependence and dominant inheritance with recruitment of wild-type protein, critical features of the altered HD property that strongly implicate them in the HD disease process and that suggest alternative pathogenic scenarios: the effect of the glutamine tract may act by altering interaction with a critical cellular constituent or by depleting a form of huntingtin essential to medium spiny striatal neurons.
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: V C
authors.initials: VC
authors.lastname: Wheeler
authors.forename: J K
authors.initials: JK
authors.lastname: White
authors.forename: C A
authors.initials: CA
authors.lastname: Gutekunst
authors.forename: V
authors.initials: V
authors.lastname: Vrbanac
authors.forename: M
authors.initials: M
authors.lastname: Weaver
authors.forename: X J
authors.initials: XJ
authors.lastname: Li
authors.forename: S H
authors.initials: SH
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Yi
authors.forename: J P
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: J F
authors.initials: JF
authors.lastname: Gusella
authors.forename: S
authors.initials: S
authors.lastname: Hersch
authors.forename: W
authors.initials: W
authors.lastname: Auerbach
authors.forename: A L
authors.initials: AL
authors.lastname: Joyner
authors.forename: M E
authors.initials: ME
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry; D005973:Glutamine / Q000235:genetics* / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D007106:Immune Sera / Q000737:chemistry; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016254:Mutagenesis, Insertional; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D012995:Solubility
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007106:Immune Sera; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D005973:Glutamine; C097188:polyglutamine