Human Molecular Genetics, 2001, Vol. 10, No. 2 137-144
© 2001 Oxford University Press
Neurological abnormalities in a knock-in mouse model of Huntington’s disease
1Department of Biochemistry and Molecular Genetics and 5Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA, 2Department of Neurology, University of Michigan and 4Geriatrics Research, Education and Clinical Center, Ann Arbor VAMC, Ann Arbor, MI 48104, USA and 3Department of Genetics, Emory University, Atlanta, GA 30322, USA
Mice representing precise genetic replicas of Huntington’s disease (HD) were made using gene targeting to replace the short CAG repeat of the mouse Huntington’s disease gene homolog (Hdh) with CAG repeats within the length range found to cause HD in humans. Mice with alleles of 
150 units in length exhibit late-onset behavioral and neuroanatomic abnormalities consistent with HD. These symptoms include a motor task deficit, gait abnormalities, reactive gliosis and the formation of neuronal intranuclear inclusions predominating in the striatum. This model differs from previously described Hdh knock-ins by its method of construction, longer repeat length and more severe phenotype. To our knowledge, this is the first knock-in mouse model of HD to show increased glial fibrillary acidic protein immunoreactivity in the striatum, suggesting that these mice have neuronal injury similar to that found early in the course of HD. These mice will serve as useful reagents in experiments designed to reveal the molecular nature of neuronal dysfunction underlying HD.
+ To whom correspondence should be addressed. Tel: +1 205 975 8157; Fax: +1 205 975 7928; Email: pdetloff@bmg.bhs.uab.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. L. Orr, S. Huang, M. A. Roberts, J. C. Reed, S. Li, and X.-J. Li Sex-dependent Effect of BAG1 in Ameliorating Motor Deficits of Huntington Disease Transgenic Mice J. Biol. Chem., June 6, 2008; 283(23): 16027 - 16036. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. Chou, J.-Y. Weng, H.-L. Lai, F. Liao, S. H. Sun, P.-H. Tu, D. W. Dickson, and Y. Chern Expanded-Polyglutamine Huntingtin Protein Suppresses the Secretion and Production of a Chemokine (CCL5/RANTES) by Astrocytes J. Neurosci., March 26, 2008; 28(13): 3277 - 3290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Wang, C.-E. Wang, A. Orr, S. Tydlacka, S.-H. Li, and X.-J. Li Impaired ubiquitin-proteasome system activity in the synapses of Huntington's disease mice J. Cell Biol., March 24, 2008; 180(6): 1177 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Orr, S. Li, C.-E. Wang, H. Li, J. Wang, J. Rong, X. Xu, P. G. Mastroberardino, J. T. Greenamyre, and X.-J. Li N-Terminal Mutant Huntingtin Associates with Mitochondria and Impairs Mitochondrial Trafficking J. Neurosci., March 12, 2008; 28(11): 2783 - 2792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gonitel, H. Moffitt, K. Sathasivam, B. Woodman, P. J. Detloff, R. L. M. Faull, and G. P. Bates DNA instability in postmitotic neurons PNAS, March 4, 2008; 105(9): 3467 - 3472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Strand, Z. C. Baquet, A. K. Aragaki, P. Holmans, L. Yang, C. Cleren, M. F. Beal, L. Jones, C. Kooperberg, J. M. Olson, et al. Expression Profiling of Huntington's Disease Models Suggests That Brain-Derived Neurotrophic Factor Depletion Plays a Major Role in Striatal Degeneration J. Neurosci., October 24, 2007; 27(43): 11758 - 11768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. DiFiglia, M. Sena-Esteves, K. Chase, E. Sapp, E. Pfister, M. Sass, J. Yoder, P. Reeves, R. K. Pandey, K. G. Rajeev, et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits PNAS, October 23, 2007; 104(43): 17204 - 17209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Y. Heng, S. J. Tallaksen-Greene, P. J. Detloff, and R. L. Albin Longitudinal Evaluation of the Hdh(CAG)150 Knock-In Murine Model of Huntington's Disease J. Neurosci., August 22, 2007; 27(34): 8989 - 8998. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kuhn, D. R. Goldstein, A. Hodges, A. D. Strand, T. Sengstag, C. Kooperberg, K. Becanovic, M. A. Pouladi, K. Sathasivam, J.-H. J. Cha, et al. Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage Hum. Mol. Genet., August 1, 2007; 16(15): 1845 - 1861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-C. Chiang, H.-M. Chen, Y.-H. Lee, H.-H. Chang, Y.-C. Wu, B.-W. Soong, C.-M. Chen, Y.-R. Wu, C.-S. Liu, D.-M. Niu, et al. Dysregulation of C/EBP{alpha} by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease Hum. Mol. Genet., March 1, 2007; 16(5): 483 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cornett, L. Smith, M. Friedman, J.-Y. Shin, X.-J. Li, and S.-H. Li Context-dependent Dysregulation of Transcription by Mutant Huntingtin J. Biol. Chem., November 24, 2006; 281(47): 36198 - 36204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lloret, E. Dragileva, A. Teed, J. Espinola, E. Fossale, T. Gillis, E. Lopez, R. H. Myers, M. E. MacDonald, and V. C. Wheeler Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice Hum. Mol. Genet., June 15, 2006; 15(12): 2015 - 2024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Van Raamsdonk, W. T. Gibson, J. Pearson, Z. Murphy, G. Lu, B. R. Leavitt, and M. R. Hayden Body weight is modulated by levels of full-length Huntingtin Hum. Mol. Genet., May 1, 2006; 15(9): 1513 - 1523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Arango, S. Holbert, D. Zala, E. Brouillet, J. Pearson, E. Regulier, A. K. Thakur, P. Aebischer, R. Wetzel, N. Deglon, et al. CA150 expression delays striatal cell death in overexpression and knock-in conditions for mutant huntingtin neurotoxicity. J. Neurosci., April 26, 2006; 26(17): 4649 - 4659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yu, N. Dadgar, M. Albertelli, A. Scheller, R. L. Albin, D. M. Robins, and A. P. Lieberman Abnormalities of Germ Cell Maturation and Sertoli Cell Cytoskeleton in Androgen Receptor 113 CAG Knock-In Mice Reveal Toxic Effects of the Mutant Protein Am. J. Pathol., January 1, 2006; 168(1): 195 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Shin, Z.-H. Fang, Z.-X. Yu, C.-E. Wang, S.-H. Li, and X.-J. Li Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity J. Cell Biol., December 19, 2005; 171(6): 1001 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Van Raamsdonk, Z. Murphy, E. J. Slow, B. R. Leavitt, and M. R. Hayden Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease Hum. Mol. Genet., December 15, 2005; 14(24): 3823 - 3835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Zeiss Neuroanatomical Phenotyping in the Mouse: The Dopaminergic System Vet. Pathol., November 1, 2005; 42(6): 753 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Iwata, J. C. Christianson, M. Bucci, L. M. Ellerby, N. Nukina, L. S. Forno, and R. R. Kopito Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation PNAS, September 13, 2005; 102(37): 13135 - 13140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Strand, A. K. Aragaki, D. Shaw, T. Bird, J. Holton, C. Turner, S. J. Tapscott, S. J. Tabrizi, A. H. Schapira, C. Kooperberg, et al. Gene expression in Huntington's disease skeletal muscle: a potential biomarker Hum. Mol. Genet., July 1, 2005; 14(13): 1863 - 1876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Warby, E. Y. Chan, M. Metzler, L. Gan, R. R. Singaraja, S. F. Crocker, H. A. Robertson, and M. R. Hayden Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo Hum. Mol. Genet., June 1, 2005; 14(11): 1569 - 1577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Van Raamsdonk, J. Pearson, D. A. Rogers, N. Bissada, A. W. Vogl, M. R. Hayden, and B. R. Leavitt Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease Hum. Mol. Genet., May 15, 2005; 14(10): 1379 - 1392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Van Raamsdonk, J. Pearson, E. J. Slow, S. M. Hossain, B. R. Leavitt, and M. R. Hayden Cognitive Dysfunction Precedes Neuropathology and Motor Abnormalities in the YAC128 Mouse Model of Huntington's Disease J. Neurosci., April 20, 2005; 25(16): 4169 - 4180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Q. Harper, P. D. Staber, X. He, S. L. Eliason, I. H. Martins, Q. Mao, L. Yang, R. M. Kotin, H. L. Paulson, and B. L. Davidson From the Cover: RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model PNAS, April 19, 2005; 102(16): 5820 - 5825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Adachi, M. Katsuno, M. Minamiyama, M. Waza, C. Sang, Y. Nakagomi, Y. Kobayashi, F. Tanaka, M. Doyu, A. Inukai, et al. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients Brain, March 1, 2005; 128(3): 659 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Everett and N. W. Wood Trinucleotide repeats and neurodegenerative disease Brain, November 1, 2004; 127(11): 2385 - 2405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Li and X.-J. Li Huntington and its Role in Neuronal Degeneration Neuroscientist, October 1, 2004; 10(5): 467 - 475. [Abstract] [PDF]
|
|
|
|
|
|
A. Khoshnan, J. Ko, E. E. Watkin, L. A. Paige, P. H. Reinhart, and P. H. Patterson Activation of the I{kappa}B Kinase Complex and Nuclear Factor-{kappa}B Contributes to Mutant Huntingtin Neurotoxicity J. Neurosci., September 15, 2004; 24(37): 7999 - 8008. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Schilling, A. V. Savonenko, A. Klevytska, J. L. Morton, S. M. Tucker, M. Poirier, A. Gale, N. Chan, V. Gonzales, H. H. Slunt, et al. Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice Hum. Mol. Genet., August 1, 2004; 13(15): 1599 - 1610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. S. Choo, G. V.W. Johnson, M. MacDonald, P. J. Detloff, and M. Lesort Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release Hum. Mol. Genet., July 15, 2004; 13(14): 1407 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gafni, E. Hermel, J. E. Young, C. L. Wellington, M. R. Hayden, and L. M. Ellerby Inhibition of Calpain Cleavage of Huntingtin Reduces Toxicity: ACCUMULATION OF CALPAIN/CASPASE FRAGMENTS IN THE NUCLEUS J. Biol. Chem., May 7, 2004; 279(19): 20211 - 20220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Ruan, M. Lesort, M. E. MacDonald, and G. V.W. Johnson Striatal cells from mutant huntingtin knock-in mice are selectively vulnerable to mitochondrial complex II inhibitor-induced cell death through a non-apoptotic pathway Hum. Mol. Genet., April 1, 2004; 13(7): 669 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Kennedy, E. Evans, C.-M. Chen, L. Craven, P. J. Detloff, M. Ennis, and P. F. Shelbourne Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis Hum. Mol. Genet., December 15, 2003; 12(24): 3359 - 3367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gines, E. Ivanova, I.-S. Seong, C. A. Saura, and M. E. MacDonald Enhanced Akt Signaling Is an Early Pro-survival Response That Reflects N-Methyl-D-aspartate Receptor Activation in Huntington's Disease Knock-in Striatal Cells J. Biol. Chem., December 12, 2003; 278(50): 50514 - 50522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. MacDonald Huntingtin: Alive and Well and Working in Middle Management Sci. Signal., November 4, 2003; 2003(207): pe48 - pe48. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Regulier, Y. Trottier, V. Perrin, P. Aebischer, and N. Deglon Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum Hum. Mol. Genet., November 1, 2003; 12(21): 2827 - 2836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhou, F. Cao, Z. Wang, Z.-X. Yu, H.-P. Nguyen, J. Evans, S.-H. Li, and X.-J. Li Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity J. Cell Biol., October 13, 2003; 163(1): 109 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Glynn, R. A. Bortnick, and A. J. Morton Complexin II is essential for normal neurological function in mice Hum. Mol. Genet., October 1, 2003; 12(19): 2431 - 2448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, T. Wyman, Z.-X. Yu, S.-H. Li, and X.-J. Li Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release Hum. Mol. Genet., August 15, 2003; 12(16): 2021 - 2030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Slow, J. van Raamsdonk, D. Rogers, S. H. Coleman, R. K. Graham, Y. Deng, R. Oh, N. Bissada, S. M. Hossain, Y.-Z. Yang, et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease Hum. Mol. Genet., July 1, 2003; 12(13): 1555 - 1567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xia, D. H. Lee, J. Taylor, M. Vandelft, and R. Truant Huntingtin contains a highly conserved nuclear export signal Hum. Mol. Genet., June 15, 2003; 12(12): 1393 - 1403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Miller, H. Xia, G. L. Marrs, C. M. Gouvion, G. Lee, B. L. Davidson, and H. L. Paulson Allele-specific silencing of dominant disease genes PNAS, June 10, 2003; 100(12): 7195 - 7200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Squitieri, C. Gellera, M. Cannella, C. Mariotti, G. Cislaghi, D. C. Rubinsztein, E. W. Almqvist, D. Turner, A.-C. Bachoud-Levi, S. A. Simpson, et al. Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course Brain, April 1, 2003; 126(4): 946 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-X. Yu, S.-H. Li, J. Evans, A. Pillarisetti, H. Li, and X.-J. Li Mutant Huntingtin Causes Context-Dependent Neurodegeneration in Mice with Huntington's Disease J. Neurosci., March 15, 2003; 23(6): 2193 - 2202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Fossale, V. C. Wheeler, V. Vrbanac, L.-A. Lebel, A. Teed, J. S. Mysore, J. F. Gusella, M. E. MacDonald, and F. Persichetti Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice Hum. Mol. Genet., September 15, 2002; 11(19): 2233 - 2241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B. Menalled, J. D. Sison, Y. Wu, M. Olivieri, X.-J. Li, H. Li, S. Zeitlin, and M.-F. Chesselet Early Motor Dysfunction and Striosomal Distribution of Huntingtin Microaggregates in Huntington's Disease Knock-In Mice J. Neurosci., September 15, 2002; 22(18): 8266 - 8276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Luthi-Carter, S. A. Hanson, A. D. Strand, D. A. Bergstrom, W. Chun, N. L. Peters, A. M. Woods, E. Y. Chan, C. Kooperberg, D. Krainc, et al. Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain Hum. Mol. Genet., August 15, 2002; 11(17): 1911 - 1926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gafni and L. M. Ellerby Calpain Activation in Huntington's Disease J. Neurosci., June 15, 2002; 22(12): 4842 - 4849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Garden, R. T. Libby, Y.-H. Fu, Y. Kinoshita, J. Huang, D. E. Possin, A. C. Smith, R. A. Martinez, G. C. Fine, S. K. Grote, et al. Polyglutamine-Expanded Ataxin-7 Promotes Non-Cell-Autonomous Purkinje Cell Degeneration and Displays Proteolytic Cleavage in Ataxic Transgenic Mice J. Neurosci., June 15, 2002; 22(12): 4897 - 4905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. P. de Almeida, C. A. Ross, D. Zala, P. Aebischer, and N. Deglon Lentiviral-Mediated Delivery of Mutant Huntingtin in the Striatum of Rats Induces a Selective Neuropathology Modulated by Polyglutamine Repeat Size, Huntingtin Expression Levels, and Protein Length J. Neurosci., May 1, 2002; 22(9): 3473 - 3483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-X. Yu, S.-H. Li, H.-P. Nguyen, and X.-J. Li Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice Hum. Mol. Genet., April 15, 2002; 11(8): 905 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. Wheeler, C.-A. Gutekunst, V. Vrbanac, L.-A. Lebel, G. Schilling, S. Hersch, R. M. Friedlander, J. F. Gusella, J.-P. Vonsattel, D. R. Borchelt, et al. Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice Hum. Mol. Genet., March 1, 2002; 11(6): 633 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Li, A. L. Cheng, H. Zhou, S. Lam, M. Rao, H. Li, and X.-J. Li Interaction of Huntington Disease Protein with Transcriptional Activator Sp1 Mol. Cell. Biol., March 1, 2002; 22(5): 1277 - 1287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Koeller, M. Woontner, L. S. Crnic, B. Kleinschmidt-DeMasters, J. Stephens, E. L. Hunt, and S. I. Goodman Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I Hum. Mol. Genet., February 1, 2002; 11(4): 347 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Laforet, E. Sapp, K. Chase, C. McIntyre, F. M. Boyce, M. Campbell, B. A. Cadigan, L. Warzecki, D. A. Tagle, P. H. Reddy, et al. Changes in Cortical and Striatal Neurons Predict Behavioral and Electrophysiological Abnormalities in a Transgenic Murine Model of Huntington's Disease J. Neurosci., December 1, 2001; 21(23): 9112 - 9123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Auerbach, M. S. Hurlbert, P. Hilditch-Maguire, Y. Z. Wadghiri, V. C. Wheeler, S. I. Cohen, A. L. Joyner, M. E. MacDonald, and D. H. Turnbull The HD mutation causes progressive lethal neurological disease in mice expressing reduced levels of huntingtin Hum. Mol. Genet., October 1, 2001; 10(22): 2515 - 2523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Yvert, K. S. Lindenberg, D. Devys, D. Helmlinger, G. B. Landwehrmeyer, and J.-L. Mandel SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types Hum. Mol. Genet., August 1, 2001; 10(16): 1679 - 1692. [Abstract] [Full Text] [PDF]
|
|
|