Abstract
BackgroundThe 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 FindingsWe 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/SignificanceComparison 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.
Highlights
Narcolepsy-cataplexy is a common sleep disorder affecting 0.02–0.16% of the general population in the United States, Europe and Asia
In the locus coeruleus (LC) where 14 genes were found to be region specific, seven, including dopamine-b-hydroxylase and tyrosine hydroxylase, are known to be expressed in the LC. These results offered a strong validation of sample selection, dissection, array experiment procedure and the statistical analysis methods used in this study. (Table S1)
insulin-like growth factor binding protein 3 (IGFBP3) inhibits hypocretin production in vivo To investigate whether IGFBP3 regulates hypocretin cell physiology and sleep in vivo, we studied IGFBP3 knockout mice [18] and two human IGFBP3 transgenic lines ( CD-1 strain) [19]: a transgenic mouse strain overexpressing human IGFBP3, and a transgenic strain overexpressing a mutated form of hIGFBP3 that does not bind IGF [20]
Summary
Narcolepsy-cataplexy is a common sleep disorder affecting 0.02–0.16% of the general population in the United States, Europe and Asia. Narcolepsy has characteristic biological markers including Human Leukocyte Antigen (HLA) association and dysfunction of hypocretin ( called orexin) neurotransmission. Almost all patients with narcolepsy-cataplexy share a common HLA allele, DQB1*0602 [1] suggesting an autoimmune basis for the disorder. The HCRT peptides are derived from a precursor, preprohypocretin, which is cleaved into two homologous peptides HCRT1 and HCRT2 [3] These act on target sites through two receptors, HCRT receptor-1 and HCRT receptor-2. 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
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