title: Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin.
abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized behaviorally by chorea, incoordination, and shortened lifespan and neuropathologically by huntingtin inclusions and neuronal degeneration. In order to facilitate studies of pathogenesis and therapeutics, we have generated a new inducible mouse model of HD expressing full-length huntingtin (Htt) using a tetracycline-regulated promoter. In double transgenic mice Htt was expressed widely in the brain under the control of the tet-transactivator (tTA) driven by the prion promoter PrP (in the absence of doxycycline). Mice expressing full-length mutant Htt, but not full-length normal Htt, displayed a progressive behavioral phenotype, consisting of slowed and irregular voluntary movements, gait ataxia, tremor and jerky movements, incoordination, and weight loss, with a shortened lifespan. Neuropathology included prominent intranuclear inclusions in cortex and striatum as well as cytoplasmic aggregates. This phenotype is very similar to the phenotypes of previous transgenic mice expressing N-terminal fragments of mutant Htt. The current HD-transgenic mice had nuclear accumulation of Htt, particularly an approximately 60-kDa fragment, which appears to represent an N-terminal cleavage product. This fragment is smaller than calpain or caspase-derived cleavage products of Htt, but it is comparable to a product, termed cp-A, which accumulates in nuclei of cells in a previously described cell model. This new mouse model may be useful in the future for pathogenic and preclinical therapeutic studies related to HD. The data suggest that proteolytic processing could be a part of the pathogenesis of HD, potentially representing an attractive therapeutic target.
authors.affiliation: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Shuichi
authors.initials: S
authors.lastname: Igarashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Juliette
authors.initials: J
authors.lastname: Gafni
authors.forename: Cameron
authors.initials: C
authors.lastname: Torcassi
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Schilling
authors.forename: Danielle
authors.initials: D
authors.lastname: Crippen
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wood
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D002467:Cell Nucleus; D004195:Disease Models, Animal; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides