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Narp immunostaining of human hypocretin (orexin) neurons

Loss in narcolepsy

From the Department of Psychiatry and Brain Research Institute (A.M. Blouin, Dr. Thannickal, and Dr. Siegel), University of California, Los Angeles, CA; the Neurobiology Research (A.M. Blouin, Dr. Thannickal, and Dr. Siegel), VA Greater Los Angeles Healthcare System, North Hills, CA; and the Departments of Neuroscience (Drs. Worley and Baraban), Neurology (Dr. Worley), and Psychiatry and Behavioral Sciences (Dr. Baraban and Reti), Johns Hopkins University School of Medicine, Baltimore, MD.

Address correspondence and reprint requests to Dr Siegel, Neurobiology Research 151A3, VA Greater Los Angeles Healthcare System, 16111 Plummer Street, North Hills, CA 91343; e-mail: jsiegel{at}ucla.edu.

Objective: To investigate whether neuronal activity-regulated pentraxin (Narp) colocalizes with hypocretin (Hcrt or orexin) in the normal human brain and to determine if Narp staining is lost in the narcoleptic human brain.

Background: Human narcolepsy is characterized by a loss of the peptide hypocretin in the hypothalamus. This loss could result from the degeneration of neurons containing hypocretin or from a more specific loss of the ability of these neurons to synthesize Hcrt. Narp has been found to colocalize with hypocretin in the rat hypothalamus.

Methods: We investigated the distribution of Narp in three normal and four narcoleptic human postmortem brains using immunohistochemistry with an antibody to Narp. Colocalization studies of Narp and hypocretin were also performed in two normal brains using immunohistochemistry with an antibody to Narp and an antibody to hypocretin.

Results: We found that Narp colocalizes with hypocretin in the lateral hypothalamic area (LHA), the dorsomedial hypothalamus (DMH), the dorsal hypothalamic area (DHA), and the posterior hypothalamic area (PHA) of the normal human. The number of Narp-positive neurons was reduced by 89% in these areas of the narcoleptic hypothalamus. In contrast, Narp staining in the paraventricular (Pa) and supraoptic nuclei (SO) of the human hypothalamus did not differ between normal and narcoleptic brains.

Conclusions: This finding supports the hypothesis that narcolepsy results from the specific loss of hypocretin neurons. Loss of hypothalamic Narp may contribute to the symptoms of narcolepsy.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the October 25 issue to find the title link for this article.

Editorial, see page 1152

See also page 1184

This article was previously published in electronic format as an Expedited E-Pub on August 31, 2005, at www.neurology.org.

Supported by NIH grants NS14610, MH64109, HL41370, the Medical Research Service of the Department of Veterans Affairs, and the Howard Hughes Medical Institute Predoctoral Fellowship (A.B.).

Disclosure: The authors report no conflicts of interest.

Submitted in preliminary form on May 19, 2004 for presentation at the Society for Neuroscience Meeting.

Presented at the Society for Neuroscience Meeting, San Diego, CA, October 24, 2004.

Received December 23, 2004. Accepted in final form June 2, 2005.

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Narcolepsy: Selective hypocretin (orexin) neuronal loss and multiple signaling deficiencies

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Neurology 2005 65: 1152-1153. [Full Text]  

Concomitant loss of dynorphin, NARP, and orexin in narcolepsy

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Neurology 2005 65: 1184-1188. [Abstract] [Full Text]  

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