Expression of Galanin and Dynorphin Decreases in Parallel with Hypocretin in Human Narcoleptic

Expression of galanin and dynorphin decreases in parallel with hypocretin in human narcoleptic hypothalami, suggesting acquired hypocretin neuron loss as the cause of hypocretin deficiency/narcolepsy syndrome. M. Honda1,2,4; A. Salehi3; Y. Honda4; P. Hesla5; J. Maehlen5; S. Tanaka1; M. Einen2; S. Gaus2,6; E. Mignot2,6 1Sleep Disorder Res, Tokyo Inst Psych, Tokyo, Japan 2Psych, 3Neurol, Stanford Univ Sch Med, Palo Alto, CA, USA 4Neuropsych Inst, Tokyo, Japan 5Pathol, Oslo Univ, Oslo, Norway 6HHMI, Palo Alto, CA, USA

The sleep disorder narcolepsy-cataplexy affects 1 in 2000 people. Its main symptoms include excessive daytime sleepiness and sudden episodes of loss of muscle tone in response to emotional stimuli (cataplexy). We and others have shown that narcolepsy is associated with undetectable levels of the hypocretin/orexin peptides, in the CSF and brain tissue. Although narcolepsy is tightly associated with HLA-DQB1*0602, suggesting an autoimmune etiology, it remains to be determined whether hypocretin neurons in the hypothalamus are genuinely damaged or quiescent, failing to produce mRNA and peptides.

Total RNA was extracted from the human hypothalami of 8 controls and 6 narcoleptic patients. Five to-8 microgram were used for each microarray experiment. Posterior and anterior hypothamic samples were processed separately. As expected, among detected transcripts, hypocretin expression was the most decreased mRNA in the posterior hypothalami of narcoleptic vs control subjects. The expression patterns of pro-dynorphin and galanin, which are known to colocalize within hypocretin neurons, were next compared with that of hypocretin. Quantitative RT-PCR experiments were performed to confirm microarray data.

We found that galanin expression pattern correlated highly with that of hypocretin. A correlation was also found for dynorphin, suggesting that expression of the neuropeptides coexpressed in hypocretin neurons changes in parallel with hypocretin deficiency in narcolepsy. Though dynorphin and galanin are not exclusively localized in hypocretin neurons, the present data supports the hypothesis of acquired hypocretin neuron death in narcolepsy.

Citation: M. Honda, A. Salehi, Y. Honda, P. Hesla, J. Maehlen, S. Tanaka, M. Einen, S. Gaus, E. Mignot. Expression of galanin and dynorphin decreases in parallel with hypocretin in human narcoleptic hypothalami, suggesting acquired hypocretin neuron loss as the cause of hypocretin deficiency/narcolepsy syndrome. Program No. 318.16. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.