IGFBP3 colocalizes with and regulates hypocretin (orexin).
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.
Honda
Makoto
M
Sleep Disorder Research Project, Tokyo Institute of Psychiatry, Setagaya, Tokyo, Japan. honda@prit.go.jp
Eriksson
Krister S
KS
Zhang
Shengwen
S
Tanaka
Susumu
S
Lin
Ling
L
Salehi
Ahmad
A
Hesla
Per Egil
PE
Maehlen
Jan
J
Gaus
Stephanie E
SE
Yanagisawa
Masashi
M
Sakurai
Takeshi
T
Taheri
Shahrad
S
Tsuchiya
Kuniaki
K
Honda
Yutaka
Y
Mignot
Emmanuel
E
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
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