title: Premature death and neurologic abnormalities in transgenic mice expressing a mutant huntingtin exon-2 fragment.
abstract: Huntington's disease (HD) is a fatal neurodegenerative disease characterized pathologically by aggregates composed of N-terminal fragments of the mutant form of the protein huntingtin (htt). The role of these N-terminal fragments in disease pathogenesis has been questioned based in part on studies in transgenic mice. In one important example, mice that express an N-terminal fragment of mutant htt terminating at the C-terminus of exon 2 (termed the Shortstop mouse) were reported to develop robust inclusion pathology without developing phenotypic abnormalities seen in the R6/2 or N171-82Q models of HD, which are also based on expression of mutant N-terminal htt fragments. To further explore the capacity of mutant exon-2 htt fragments to produce neurologic abnormalities (N-terminal 118 amino acids; N118), we generated transgenic mice expressing cDNA that encodes htt N118-82Q with the mouse prion promoter vector. In mice generated in this manner, we demonstrate robust inclusion pathology accompanied by early death and failure to gain weight. These phenotypes are the most robust abnormalities identified in the R6/2 and N171-82Q models. We conclude that the lack of an overt phenotype in the initial Shortstop mice cannot be completely explained by the properties of mutant htt N118 fragments.
authors.affiliation: Department of Neuroscience, SantaFe HealthCare Alzheimer's Disease Research Center, McKnight Brain Institute, University of Florida, 100 Newell Dr, Rm. L1-100, Gainesville, FL 32610, USA.
authors.forename: Andrew T N
authors.initials: AT
authors.lastname: Tebbenkamp
authors.forename: Debbie
authors.initials: D
authors.lastname: Swing
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000002:abnormalities / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons; D006801:Humans; D000071058:Huntingtin Protein; D002479:Inclusion Bodies / Q000378:metabolism; D008017:Life Expectancy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins