IGFBP3 colocalizes with and regulates hypocretin (orexin)

Makoto Honda, Krister S. Eriksson, Shengwen Zhang, Susumu Tanaka, Ling Lin, Ahmad Salehi, Per Egil Hesla, Jan Maehlen, Stephanie E. Gaus, Masashi Yanagisawa, Takeshi Sakurai, Shahrad Taheri, Kuniaki Tsuchiya, Yutaka Honda, Emmanuel Mignot

Research output: Contribution to journalArticle

46 Citations (Scopus)

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. Methodology/Principal Findings: 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 coexpressed 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/Significance: 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.

Original languageEnglish
Article numbere4254
JournalPLoS One
Volume4
Issue number1
DOIs
Publication statusPublished - 22 Jan 2009
Externally publishedYes

Fingerprint

Insulin-Like Growth Factor Binding Protein 3
insulin-like growth factor binding proteins
Narcolepsy
neurons
hypothalamus
Neurons
sleep
brain
transcriptome
Brain
Functional analysis
Genes
mice
adolescence
animal models
Polymorphism
Transcriptome
Gene expression
genetic polymorphism
genetically modified organisms

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Honda, M., Eriksson, K. S., Zhang, S., Tanaka, S., Lin, L., Salehi, A., ... Mignot, E. (2009). IGFBP3 colocalizes with and regulates hypocretin (orexin). PLoS One, 4(1), [e4254]. https://doi.org/10.1371/journal.pone.0004254

IGFBP3 colocalizes with and regulates hypocretin (orexin). / Honda, Makoto; Eriksson, Krister S.; Zhang, Shengwen; Tanaka, Susumu; Lin, Ling; Salehi, Ahmad; Hesla, Per Egil; Maehlen, Jan; Gaus, Stephanie E.; Yanagisawa, Masashi; Sakurai, Takeshi; Taheri, Shahrad; Tsuchiya, Kuniaki; Honda, Yutaka; Mignot, Emmanuel.

In: PLoS One, Vol. 4, No. 1, e4254, 22.01.2009.

Research output: Contribution to journalArticle

Honda, M, Eriksson, KS, Zhang, S, Tanaka, S, Lin, L, Salehi, A, Hesla, PE, Maehlen, J, Gaus, SE, Yanagisawa, M, Sakurai, T, Taheri, S, Tsuchiya, K, Honda, Y & Mignot, E 2009, 'IGFBP3 colocalizes with and regulates hypocretin (orexin)', PLoS One, vol. 4, no. 1, e4254. https://doi.org/10.1371/journal.pone.0004254
Honda M, Eriksson KS, Zhang S, Tanaka S, Lin L, Salehi A et al. IGFBP3 colocalizes with and regulates hypocretin (orexin). PLoS One. 2009 Jan 22;4(1). e4254. https://doi.org/10.1371/journal.pone.0004254
Honda, Makoto ; Eriksson, Krister S. ; Zhang, Shengwen ; Tanaka, Susumu ; Lin, Ling ; Salehi, Ahmad ; Hesla, Per Egil ; Maehlen, Jan ; Gaus, Stephanie E. ; Yanagisawa, Masashi ; Sakurai, Takeshi ; Taheri, Shahrad ; Tsuchiya, Kuniaki ; Honda, Yutaka ; Mignot, Emmanuel. / IGFBP3 colocalizes with and regulates hypocretin (orexin). In: PLoS One. 2009 ; Vol. 4, No. 1.
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AU - Salehi, Ahmad

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