Narp immunostaining of human hypocretin (orexin) neurons - Loss in narcolepsy

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, United States
Neurology (Impact Factor: 8.29). 11/2005; 65(8):1189-92. DOI: 10.1212/01.wnl.0000175219.01544.c8
Source: PubMed


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.
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.
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.
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.
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.

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    • "These include cataplexy (sudden loss of muscle tone triggered by strong emotions), sleep paralysis, hypnagogic hallucinations, and sleep-onset REM periods (SOREMP). Recent pathophysiological insights have demonstrated that NC is caused by the early loss of hypothalamic neurons producing hypocretin/orexin [2] [3] [4] [5]. A striking decrease in cerebrospinal fluid (CSF) hypocretin-1 concentrations has been noted in most of those patients with a high (94%) positive predictive value for the diagnosis of NC [6] [7]. "
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    • "RESEARCH ARTICLE Development (2015) 142, 633-643 doi:10.1242/dev.117978 DEVELOPMENT dynorphin A (DYNA) and the neuronal pentraxin NPTX2 (NARP), which are expressed in nearly all mouse and human HCRT neurons in vivo (Blouin et al., 2005; Chou et al., 2001; Crocker et al., 2005). We observed that 54/55 in vitro-derived HCRTA-immunopositive neurons expressed PDYN (Fig. 6D) and that 43/50 of HCRTAimmunopositive cells expressed NPTX2 with the punctate pattern this AMPA receptor-associated protein characteristically shows in vivo (O'Brien et al., 1999) (Fig. 6E). "
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    ABSTRACT: Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agouti-related peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone. Hypothalamic neurons can be generated using a 'self-patterning' strategy that yields a broad array of cell types, or via a more reproducible directed differentiation approach. Stem cell-derived human hypothalamic neurons share characteristic morphological properties and gene expression patterns with their counterparts in vivo, and are able to integrate into the mouse brain. These neurons could form the basis of cellular models, chemical screens or cellular therapies to study and treat common human diseases. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(4):633-43. DOI:10.1242/dev.117978 · 6.46 Impact Factor
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    • "Further research has demonstrated that approximately 90% of the orexin-producing neurons are lost in human narcolepsy with cataplexy. The endogenous opiate dynorphin and NARP (a protein involved in glutamate signalling) are also produced by the orexin neurons, and both of these markers are absent in the lateral hypothalamus of patients with narcolepsy (Blouin et al., 2005; Crocker et al., 2005). This cell loss seems highly selective as neurons producing melanin-concentrating hormone (MCH), which are intermingled with the orexin neurons, seem completely unaffected (Peyron et al., 2000; Thannickal et al., 2000). "
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2012; 32(36):12305-11. DOI:10.1523/JNEUROSCI.2630-12.2012 · 6.34 Impact Factor
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