Narp immunostaining of human hypocretin (orexin) neurons - Loss in narcolepsy
ABSTRACT 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.
- SourceAvailable from: Florian Merkle
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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). "
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 · 6.27 Impact Factor
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 · 6.75 Impact Factor
- "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). "
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- "NARP is a synaptic signaling protein that stimulates clustering of glutamatergic AMPA receptors (Tsui et al. 1996, Fong and Craig 1999, O'Brien et al. 1999). The orexin neurons of mice and humans express NARP (Reti et al. 2002, Blouin et al. 2005, Crocker et al. 2005), and it is possible that the NARP itself potentiates pre-or post-synaptic responses to glutamate. "
ABSTRACT: The orexin neurones play an essential role in driving arousal and in maintaining normal wakefulness. Lack of orexin neurotransmission produces a chronic state of hypoarousal characterized by excessive sleepiness, frequent transitions between wake and sleep, and episodes of cataplexy. A growing body of research now suggests that the basal forebrain (BF) may be a key site through which the orexin-producing neurones promote arousal. Here we review anatomical, pharmacological and electrophysiological studies on how the orexin neurones may promote arousal by exciting cortically projecting neurones of the BF. Orexin fibres synapse on BF cholinergic neurones and orexin-A is released in the BF during waking. Local application of orexins excites BF cholinergic neurones, induces cortical release of acetylcholine and promotes wakefulness. The orexin neurones also contain and probably co-release the inhibitory neuropeptide dynorphin. We found that orexin-A and dynorphin have specific effects on different classes of BF neurones that project to the cortex. Cholinergic neurones were directly excited by orexin-A, but did not respond to dynorphin. Non-cholinergic BF neurones that project to the cortex seem to comprise at least two populations with some directly excited by orexin-A that may represent wake-active, GABAergic neurones, whereas others did not respond to orexin-A but were inhibited by dynorphin and may be sleep-active, GABAergic neurones. This evidence suggests that the BF is a key site through which orexins activate the cortex and promote behavioural arousal. In addition, orexins and dynorphin may act synergistically in the BF to promote arousal and improve cognitive performance.Acta Physiologica 10/2009; 198(3):223-35. DOI:10.1111/j.1748-1716.2009.02036.x · 4.25 Impact Factor