title: Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice.
abstract: Huntington's disease (HD) results from the expansion of a glutamine repeat near the N-terminus of huntingtin (htt). At post-mortem, neurons in the central nervous system of patients have been found to accumulate N-terminal fragments of mutant htt in nuclear and cytoplasmic inclusions. This pathology has been reproduced in transgenic mice expressing the first 171 amino acids of htt with 82 glutamines along with losses of motoric function, hypoactivity and abbreviated life-span. The relative contributions of nuclear versus cytoplasmic mutant htt to the pathogenesis of disease have not been clarified. To examine whether pathogenic processes in the nucleus disproportionately contribute to disease features in vivo, we fused a nuclear localization signal (NLS) derived from atrophin-1 to the N-terminus of an N171-82Q construct. Two lines of mice (lines 8A and 61) that were identified expressed NLS-N171-82Q at comparable levels and developed phenotypes identical to our previously described HD-N171-82Q mice. Western blot and immunohistochemical analyses revealed that NLS-N171-82Q fragments accumulate in nuclear, but not cytoplasmic, compartments. These data suggest that disruption of nuclear processes may account for many of the disease phenotypes displayed in the mouse models generated by expressing mutant N-terminal fragments of htt.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. gschill1@jhmi.edu
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schilling
authors.forename: Alena V
authors.initials: AV
authors.lastname: Savonenko
authors.forename: Alexandra
authors.initials: A
authors.lastname: Klevytska
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Morton
authors.forename: Stina M
authors.initials: SM
authors.lastname: Tucker
authors.forename: Michelle
authors.initials: M
authors.lastname: Poirier
authors.forename: Alexa
authors.initials: A
authors.lastname: Gale
authors.forename: Ning
authors.initials: N
authors.lastname: Chan
authors.forename: Vicky
authors.initials: V
authors.lastname: Gonzales
authors.forename: Hilda H
authors.initials: HH
authors.lastname: Slunt
authors.forename: Michael L
authors.initials: ML
authors.lastname: Coonfield
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000367:Age Factors; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005822:Genetic Vectors; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments