title: Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates.
abstract: Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the down-regulation of specific genes in this region of the brain.
authors.affiliation: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Kotliarova
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Jana
authors.forename: Naoaki
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.forename: Haruko
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Munenori
authors.initials: M
authors.lastname: Nekooki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Machida
authors.forename: Hon Kit
authors.initials: HK
authors.lastname: Wong
authors.forename: Taishi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Chiharu
authors.initials: C
authors.lastname: Uchikawa
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kotliarov
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Uchida
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Nagao
authors.forename: Utako
authors.initials: U
authors.lastname: Nagaoka
authors.forename: Akira
authors.initials: A
authors.lastname: Tamaoka
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Oyanagi
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Oyama
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D010121:Oxytocin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014667:Vasopressins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D014667:Vasopressins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D010121:Oxytocin