Journal Article

IGFBP3 Colocalizes with and Regulates Hypocretin (Orexin)

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

2009

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adolescence / Adolescents / Adult / Analysis / Animal models / Animals / Antibodies / Autoantibodies / Autoimmunity / Brain / Brain - metabolism / Brain research / Cell Death / Cercopithecus aethiops / Cerebrospinal fluid / COS Cells / DNA microarrays / Enzymes / Female / Functional analysis / Gene expression / Gene Expression Regulation / Genes / Genetic engineering / Genetic polymorphisms / Genetics and Genomics/Animal Genetics / Genetics and Genomics/Genetics of Disease / Genomes / Growth factors / Histocompatibility antigen HLA / Humans / Hypothalamus / Hypothalamus - metabolism / Hypotheses / Immunoassay / Insulin / Insulin-Like Growth Factor Binding Protein 3 / Insulin-Like Growth Factor Binding Proteins - metabolism / Intracellular Signaling Peptides and Proteins - metabolism / Male / Metabolism / Mice / Mice, Inbred C57BL / Mice, Transgenic / Middle Aged / mRNA / Narcolepsy / Narcolepsy - metabolism / Neurons / Neuropeptides / Neuropeptides - metabolism / Neuroscience / Neuroscience/Neurobiology of Disease and Regeneration / Orexins / Pathology/Neuropathology / Peptides / Physiological aspects / Physiology / Polymorphism / Protein binding / Proteins / Psychiatry / Quality control / Ribonucleic acid / RNA / Rodents / Sleep / Sleep disorders / Studies / Transgenic mice