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IGFBP3 colocalizes with and regulates hypocretin (orexin)
Makoto Honda1, Krister S Eriksson, Shengwen Zhang
1Sleep Disorder Research Project, Tokyo Institute of Psychiatry, Setagaya, Tokyo, Japan. honda@prit.go.jp
Plos One
|January 23, 2009
Summary
Narcolepsy involves hypocretin (orexin) neuron loss. Researchers identified insulin-like growth factor binding protein 3 (IGFBP3) as a novel regulator of hypocretin cell function, potentially involved in narcolepsy development.
Area of Science:
- Neuroscience
- Genetics
- Sleep Medicine
Background:
- Narcolepsy is a sleep disorder characterized by a significant loss of hypocretin (orexin) producing neurons.
- The exact cause of hypocretin cell loss in narcolepsy remains unknown, despite its association with HLA.
- Investigating gene expression in the hypothalamus may reveal targets of autoimmune attack or modulators of hypocretin expression.
Purpose of the Study:
- To identify novel genes dysregulated in the hypothalamus of narcolepsy patients and a mouse model.
- To explore the role of dysregulated genes in hypocretin cell function and narcolepsy pathophysiology.
Main Methods:
- Gene expression profiling using microarrays in postmortem human brains (narcoleptic vs. control) and transgenic mice (hypocretin-deficient vs. wild type).
- Analysis of gene co-expression and localization within hypocretin neurons.
- Functional studies in mice to assess the impact of IGFBP3 on hypocretin levels and sleep.
Main Results:
- Hypocretin was the most downregulated gene in human narcolepsy brains.
- Insulin-like growth factor binding protein 3 (IGFBP3) was downregulated in both human and mouse models and co-expressed in hypocretin neurons.
- Overexpression of IGFBP3 in mice decreased hypocretin mRNA and peptide, increased sleep, and potentially reduced hypocretin promoter activity.
Conclusions:
- IGFBP3 is a novel regulator of hypocretin cell physiology, identified through comparative transcriptomic analysis.
- IGFBP3 may play a role in narcolepsy pathophysiology and normal sleep regulation, particularly in adolescents.
- Further research is needed to confirm if excessive IGFBP3 expression triggers hypocretin cell death and causes narcolepsy.
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