title: IGFBP3 colocalizes with and regulates hypocretin (orexin).
abstract: BACKGROUND
  The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression.
  
  
  RESULTS
  We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals.
  
  
  CONCLUSIONS
  Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.
authors.affiliation: Sleep Disorder Research Project, Tokyo Institute of Psychiatry, Setagaya, Tokyo, Japan. honda@prit.go.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Honda
authors.forename: Krister S
authors.initials: KS
authors.lastname: Eriksson
authors.forename: Shengwen
authors.initials: S
authors.lastname: Zhang
authors.forename: Susumu
authors.initials: S
authors.lastname: Tanaka
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salehi
authors.forename: Per Egil
authors.initials: PE
authors.lastname: Hesla
authors.forename: Jan
authors.initials: J
authors.lastname: Maehlen
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Gaus
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Shahrad
authors.initials: S
authors.lastname: Taheri
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Honda
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D016923:Cell Death; D002522:Chlorocebus aethiops; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009290:Narcolepsy / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins
chemical_list: C000596229:HCRT protein, human; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins