title: Early white matter abnormalities, progressive brain pathology and motor deficits in a novel knock-in mouse model of Huntington's disease.
abstract: White matter abnormalities have been reported in premanifest Huntington's disease (HD) subjects before overt striatal neuronal loss, but whether the white matter changes represent a necessary step towards further pathology and the underlying mechanism of these changes remains unknown. Here, we characterized a novel knock-in mouse model that expresses mouse HD gene homolog (Hdh) with extended CAG repeat- HdhQ250, which was derived from the selective breeding of HdhQ150 mice. HdhQ250 mice manifest an accelerated and robust phenotype compared with its parent line. HdhQ250 mice exhibit progressive motor deficits, reduction in striatal and cortical volume, accumulation of mutant huntingtin aggregation, decreased levels of DARPP32 and BDNF and altered striatal metabolites. The abnormalities detected in this mouse model are reminiscent of several aspects of human HD. In addition, disturbed myelination was evident in postnatal Day 14 HdhQ250 mouse brain, including reduced levels of myelin regulatory factor and myelin basic protein, and decreased numbers of myelinated axons in the corpus callosum. Thinner myelin sheaths, indicated by increased G-ratio of myelin, were also detected in the corpus callosum of adult HdhQ250 mice. Moreover, proliferation of oligodendrocyte precursor cells is altered by mutant huntingtin both in vitro and in vivo. Our data indicate that this model is suitable for understanding comprehensive pathogenesis of HD in white matter and gray matter as well as developing therapeutics for HD.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences.
authors.forename: Qi
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Radiology and.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences.
authors.forename: Mali
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neuroscience.
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Langseth
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences.
authors.forename: Michael
authors.initials: M
authors.lastname: Tao
authors.affiliation: Department of Radiology and.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Barker
authors.affiliation: Department of Radiology and.
authors.forename: Susumu
authors.initials: S
authors.lastname: Mori
authors.affiliation: Department of Neuroscience.
authors.forename: Dwight E
authors.initials: DE
authors.lastname: Bergles
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA, Department of Neuroscience, Department of Neurology and Pharmacology and Molecular Sciences and.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35242, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Detloff
authors.affiliation: Department of Radiology and.
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA, Department of Neuroscience, wduan2@jhmi.edu.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
mesh_terms: D000483:Alleles; D000818:Animals; D001284:Atrophy; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D009929:Organ Size; D066263:Protein Aggregation, Pathological; D066127:White Matter / Q000378:metabolism / Q000473:pathology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins