title: Longitudinal evaluation of the Hdh(CAG)150 knock-in murine model of Huntington's disease.
abstract: Several murine genetic models of Huntington's disease (HD) have been developed. Murine genetic models are crucial for identifying mechanisms of neurodegeneration in HD and for preclinical evaluation of possible therapies for HD. Longitudinal analysis of mutant phenotypes is necessary to validate models and to identify appropriate periods for analysis of early events in the pathogenesis of neurodegeneration. Here we report longitudinal characterization of the murine Hdh(CAG)150 knock-in model of HD. A series of behavioral tests at five different time points (20, 40, 50, 70, and 100 weeks) demonstrates an age-dependent, late-onset behavioral phenotype with significant motor abnormalities at 70 and 100 weeks of age. Pathological analysis demonstrated loss of striatal dopamine D1 and D2 receptor binding sites at 70 and 100 weeks of age, and stereological analysis showed significant loss of striatal neuron number at 100 weeks. Late-onset behavioral abnormalities, decrease in striatal dopamine receptors, and diminished striatal neuron number observed in this mouse model recapitulate key features of HD. The Hdh(CAG)150 knock-in mouse is a valid model to evaluate early events in the pathogenesis of neurodegeneration in HD.
authors: Neuroscience Graduate Program and Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Mary Y
authors: MY
authors: Heng
authors: Sara J
authors: SJ
authors: Tallaksen-Greene
authors: Peter J
authors: PJ
authors: Detloff
authors: Roger L
authors: RL
authors: Albin
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D019417:Hindlimb Suspension / Q000379:methods; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D011954:Receptors, Dopamine / Q000378:metabolism; D015203:Reproducibility of Results; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011954:Receptors, Dopamine; D010751:Phosphopyruvate Hydratase
references: Diabetes. 1999 Mar;48(3):649-51
references: 10078572
references: J Neurosci. 1999 Apr 15;19(8):3248-57
references: 10191337
references: Hum Mol Genet. 1999 May;8(5):763-74
references: 10196365
references: Neuron. 1999 May;23(1):181-92
references: 10402204
references: Hum Mol Genet. 2000 Mar 1;9(4):503-13
references: 10699173
references: Hum Mol Genet. 2000 Apr 12;9(6):909-16
references: 10767314
references: Neurology. 2000 May 9;54(9):1753-9
references: 10802780
references: Hum Mol Genet. 2001 Jan 15;10(2):137-44
references: 11152661
references: Genes Dev. 2001 Apr 15;15(8):925-32
references: 11316786
references: Neurology. 2002 Mar 12;58(5):695-701
references: 11889230
references: J Comp Neurol. 2002 Jul 29;449(3):241-69
references: 12115678
references: Brain. 2003 Apr;126(Pt 4):946-55
references: 12615650
references: J Neurosci. 2003 Mar 15;23(6):2193-202
references: 12657678
references: Neurology. 2003 May 27;60(10):1615-20
references: 12771251
references: Hum Mol Genet. 2003 Jul 1;12(13):1555-67
references: 12812983
references: J Comp Neurol. 2003 Oct 6;465(1):11-26
references: 12926013
references: J Comp Neurol. 2003 Oct 13;465(2):205-19
references: 12949782
references: Trends Mol Med. 2003 Oct;9(10):414-20
references: 14557053
references: Neurology. 2004 Jul 13;63(1):66-72
references: 15249612
references: Eur J Neurosci. 2004 Dec;20(11):3092-114
references: 15579164
references: Neuroscience. 2005;131(4):843-52
references: 15749339
references: Brain Res. 2005 Mar 28;1039(1-2):14-21
references: 15781041
references: Eur J Neurosci. 2005 Feb;21(4):855-70
references: 15787692
references: J Comp Neurol. 2005 Oct 3;490(4):354-70
references: 16127709
references: Neurobiol Dis. 2005 Oct;20(1):1-11
references: 16137562
references: Neurology. 2005 Sep 13;65(5):745-7
references: 16157910
references: Neurology. 2005 Sep 27;65(6):941-3
references: 16186542
references: J Neurochem. 2006 Jun;97(6):1690-9
references: 16805777
references: Neurobiol Dis. 2007 Feb;25(2):297-308
references: 17126554
references: Neurobiol Dis. 2007 Apr;26(1):189-200
references: 17276692
references: Hum Mol Genet. 2007 Aug 1;16(15):1845-61
references: 17519223
references: Nature. 1991 Jul 4;352(6330):77-9
references: 2062380
references: Proc Natl Acad Sci U S A. 1988 Aug;85(15):5733-7
references: 2456581
references: Ann Neurol. 1994 Sep;36(3):443-7
references: 8080254
references: Cell. 1993 Mar 26;72(6):971-83
references: 8458085
references: J Neurol Neurosurg Psychiatry. 1996 Mar;60(3):354-6
references: 8609529
references: Ann Neurol. 1996 Jul;40(1):49-54
references: 8687191
references: Cell. 1996 Nov 1;87(3):493-506
references: 8898202
references: Brain. 1997 Mar;120 ( Pt 3):503-14
references: 9126061
references: Brain. 1997 Dec;120 ( Pt 12):2207-17
references: 9448576
references: Pain. 1998 Apr;75(2-3):355-65
references: 9583772
references: J Neuropathol Exp Neurol. 1998 May;57(5):369-84
references: 9596408
references: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6480-5
references: 9600992
references: Nat Genet. 1998 Oct;20(2):198-202
references: 9771716
references: Hum Mol Genet. 1999 Mar;8(3):397-407
references: 9949199