title: Longitudinal behavioral, cross-sectional transcriptional and histopathological characterization of a knock-in mouse model of Huntington's disease with 140 CAG repeats.
abstract: The discovery of the gene mutation responsible for Huntington's disease (HD), huntingtin, in 1993 allowed for a better understanding of the pathology of and enabled the development of animal models. HD is caused by the expansion of a polyglutamine repeat region in the N-terminal of the huntingtin protein. Here we examine the behavioral, transcriptional, histopathological and anatomical characteristics of a knock-in HD mouse model with a 140 polyglutamine expansion in the huntingtin protein. This CAG 140 model contains a portion of the human exon 1 with 140 CAG repeats knocked into the mouse huntingtin gene. We have longitudinally examined the rearing behavior, accelerating rotarod, constant speed rotarod and gait for age-matched heterozygote, homozygote and non-transgenic mice and have found a significant difference in the afflicted mice. However, while there were significant differences between the non-transgenic and the knock-in mice, these behaviors were not progressive. As in HD, we show that the CAG 140 mice also have a significant decrease in striatally enriched mRNA transcripts. In addition, striatal neuronal intranuclear inclusion density increases with age. Lastly these CAG 140 mice show slight cortical thinning compared to non-transgenic mice, similarly to the cortical thinning recently reported in HD.
authors.affiliation: Department of Neuroscience, Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, PO Box 100244, Gainesville, FL 32610, USA.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Rising
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.forename: Aaron
authors.initials: A
authors.lastname: Carlson
authors.forename: Vincent V
authors.initials: VV
authors.lastname: Napoli
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Denovan-Wright
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Mandel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003430:Cross-Sectional Studies; D004195:Disease Models, Animal; D005260:Female; D005684:Gait / Q000235:genetics; D055879:Gene Knock-In Techniques / Q000379:methods*; D006580:Genetic Carrier Screening / Q000379:methods; D006720:Homozygote; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D045442:Rotarod Performance Test; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins