title: Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington's disease knock-in mice.
abstract: Huntington's disease (HD) is characterized by a progressive loss of neurons in the striatum and cerebral cortex and is caused by a CAG repeat expansion in the gene encoding huntingtin. Mice with the mutation inserted into their own huntingtin gene (knock-in mice) are, genetically, the best models of the human disease. Here we show for the first time that knock-in mice with 94 CAG repeats develop a robust and early motor phenotype at 2 months of age, characterized by increased rearing at night. This initial increase in repetitive movements was followed by decreased locomotion at 4 and 6 months, despite a normal life span. The decrease in striatal enkephalin mRNA that is known to occur at 4 months was not present at 2 months, when increased rearing was observed. Both the hyperactive and hypoactive phases of motor dysfunction preceded the detection of nuclear microaggregates of mutated huntingtin in striatal neurons. Nuclear microaggregates, defined as small huntingtin-positive punctas detected by light microscopy, were very rare at 4 months but became widely distributed in striatal neurons at 6 months. Nuclear inclusions did not appear until 18 months. When present, nuclear microaggregates predominated in the striosomal compartment of the striatum, providing a possible explanation for the different neuronal vulnerability of striatal compartments observed in humans. The early motor phenotype observed in the knock-in mouse is reminiscent of repetitive movements often observed in early HD and provides a novel opportunity to assess the ability of therapies to prevent the initial effects of the mutation in vivo.
authors.affiliation: Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California 90095, USA.
authors.forename: Liliana B
authors.initials: LB
authors.lastname: Menalled
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Sison
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Melisa
authors.initials: M
authors.lastname: Olivieri
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Scott
authors.initials: S
authors.lastname: Zeitlin
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Chesselet
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006120:Grooming; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002479:Inclusion Bodies / Q000378:metabolism* / Q000648:ultrastructure; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D017450:Receptors, Opioid, mu / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D004745:Enkephalins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu