Background of Narcolepsy

Narcolepsy is a neurological disorder and a common cause of chronic sleepiness. Typically starting in adolescence, it affects about 1 in 20,000 people and in 24% of the affected individuals it can lead to disability [1 [2]. Most of the time, individuals with narcolepsy are observed to have symptoms including odd mixtures of sleep and wakefulness [1]. They tend to experience excessive daytime sleepiness and various other symptoms such as sleep paralysis, hypnagogic hallucinations and cataplexy [1]. A pair of neuropeptides have been discovered and termed hypocretin-1 and -2 (also referred to as orexin A and B), and they are produced in hypothalamic neurons [3]. These neuropeptides are ligands that go along with the two G-protein coupled receptors, known as OX1 and OX2 [3]. The hypocretinergic system is thought to play a vital role in the regulation of sleep/wake behaviour [3]. As a result, narcolepsy has been associated with the loss of hypothalamic hypocretin-producing neurons in the lateral hypothalamus [2]. Cell loss in this region is thought to be selective because neurons such as melanin-concentrating hormone (MCH) seem to be unaffected, while endogenous opiate dynorphin and NARP (protein involved in glutamate signaling) are absent in the lateral hypothalamus of patients affected [1].

1. Hypocretin Neuropeptides

1.1. Orexin A and Orexin B

The neuropeptides orexin A and orexin B are also known as hypocretin 1 and hypocretin 2, respectively were discovered in 1998 [3 [4]. These neuropeptides are produced in hypothalamic neurons and were originally recognized for being exclusively produced in the lateral hypothalamic area (LHA) [3]. These neurons innervate a number of structures within the central nervous system (CNS) as they are the center of an extensive projection system [4]. The LHA is known as the feeding center and thus these neuropeptides have been associated with being regulators of feeding behaviour [3]. These neuropeptides are also involved in the regulation of various other organic functions including thermoregulation, and neuroendocrine and cardiovascular control [4]. Initially, they were identified as being endogenous ligands for two orphan G-protein-coupled receptors, but subsequently there has been a demonstration of the importance of orexins in the maintenance of sleep/wake cycles [3]. Narcolepsy, being a sleep disorder, is thought to be caused by a deficiency of orexin in both humans and animals [3].
Both orexin A and B are derived from pre-pro-hypocretin, which is a common precursor peptide (figure 1) [4]. Pre-pro-hypocretin is cleaved at specific sites that contain basic amino acid residues following the removal of the secretory signal sequence on the N-terminal [4]. This results in two mature peptides; orexin A has two disulfide bridges in comparison to orexin B which is linear [4]. Mediated through the interaction of G-protein-coupled receptors, the functions of the neuropeptides are region specific within the CNS [4].

Schematic of hypocretin system
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Shows that pre-pro-hypocretin is cleaved to form two mature peptides, which then interact with G-protein-coupled receptors. Figure from [4].

2. Immune-mediated disease

2.1. Immune system, autoimmunity and narcolepsy

Narcolepsy has a strong genetic association with selected human leukocyte antigen (HLA) alleles with more than 98% of patients who have low cerebrospinal fluid (CSF) hypocretin-1, carrying HLA DQBI*06:02, and quite often in combination with HLA DRBI*15:01 [2 [5]. As a result of this; there is a suspected autoimmune basis for the loss of hypocretin/orexin cells in those with narcolepsy [2]. These alleles can encode numerous subtypes of Major Histocompatibility Complex (MHC) classes I and II proteins [2]. An immune response is triggered upon T-cell receptor (TCR) activation and this occurs when foreign peptides are presented on MHC proteins to T cells, during infections [2]. Several autoimmune diseases such as Graves’s disease, rheumatoid arthritis, and type 1 diabetes have been associated with HLA class II encoded HLA-DRB1-DQA1-DQB1 haplotype [5]. Depletion of hypocretin producing neurons can be due to the association with DQB1*06:02 which can be suggestive of an interaction with a T cell receptor subtype [5]. In regard to autoimmunity, the hypothesis is that self-peptides are mistakenly recognized as foreign; this consequently leads to the destruction of hypocretin tissue and often in the context of HLA alleles [2].

2.2. Molecular mimicry and H1N1 pandemic and vaccinations

The existence of structural similarities between antigenic determinants of a pathogen and the host is the hypothesis that shapes the concept of molecular mimicry [2]. One single T cell receptor has the ability to bind to various antigens that are structurally similar and bound to one or numerous MHC molecules [2]. When a T cell responds to pathogen specific antigens, in the process it may lead to the activation and expansion of T cells that are cross-reactive with self-antigens [2]. In regard to narcolepsy, bacterial and/or viral peptides would have to be processed and presented in the context of MHC DQB1*06:02; in order to relate to the concept of molecular mimicry. This would result in the activation of a population of cross-reactive T cells that are present in predisposed persons [2].
Natural infection has an increased degree (such as affinity, strength of T cell response and the cytokines that are released), longer duration, and greater dispersion of inflammation [6]. Designed to produce a shorter duration of controlled immune stimulation that results in minimal cell damage are vaccines which can be comparable to natural infections [6]. Molecular mimicry can be stimulated by natural infections [2].Findings suggest that hypocretin-producing neurons can be depleted due to the activation of particular T cells by H1N1 epitopes [2]. A critical component for vaccine safety is controlling the immune stimulation by an adjuvant; however, it is extremely vital to make sure that the antigens selected for the vaccine do not include microbial proteins that may be molecular mimics of autoantigens [6].

Molecular Mimicry
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At the MHC/TCR synapse level. Figure from [2].

3. Past Research

3.1. Effects of intranasal hypocretin-1 on sleep in narcolepsy with cataplexy

The neuropeptides hypocretin-1 and -2 have been identified as playing a crucial role in the regulation of sleep/wake cycle. This study tests the hypothesis that intranasal application of hypocretin-1 tends to increase wakefulness and reduce REM sleep in an individual who has narcolepsy with cataplexy and is hypocretin-1 deficient [7]. They found that hypocretin-1 has functional effects on sleep in those with narcolepsy with cataplexy [7]. The intranasal administration of hypocretin-1 did not have any statistically significant effect on nocturnal wakefulness [7]. However, the administration did reduce the amount of REM sleep and exerted an evident REM sleep stabilizing effect [7]. This study is important as it may help in future studies having to do with the hypocretinergic system and its effects. In addition, it can be helpful in the development of prospective treatment for the disease.

3.2. Glucose tolerance in patients with narcolepsy

Hypocretin1 and 2 are derived from a common precursor peptide [4]. They are known to be associated with the regulation of arousal, appetite, and various endocrine and metabolic networks including glycemic control [8]. Being involved in the regulation of appetite leads to the concept of obesity and increased body weight is seen as a common feature of human narcolepsy [8]. Mice that were genetically engineered to lose hypocretin neurons at the time of postnatal development were observed to display obesity in adulthood without much change in food intake [8]. This experiment tested whether glucose metabolism is disturbed as a result of, or independently of obesity in patients with narcolepsy [8]. Patients with narcolepsy compared to healthy controls were studied by performing an oral glucose tolerance test (OGTT). Glucose tolerance was computed by plasma glucose curves and there was no clinically relevant pathologic finding between the controls and the patients with narcolepsy [8]. The study concluded that narcolepsy is probably not a risk factor leading to impaired glucose tolerance or diabetes [8].

4. Future Direction

Disrupted nighttime sleep (DNS) is a common aspect of narcolepsy, but appears to be different from disrupted nighttime sleep in other sleep disorders [9]. DNS in narcolepsy can be characterized as frequent brief awakenings, mainly by patient reports[9]. A future aspect in relation to DNS can be in studies that are needed in order to evaluate different kinds of therapies on the treatment of DNS, focusing on effects experienced by patients.
Some future research aspects as addressed by Sahota include pathophysiological, etiological, therapeutic and genetic implications in regard to narcolepsy [10].In terms of etiology, the mechanism by which hypocretin neurons are lost is still not completely understood, thus requiring further studies [10]. The understanding is that narcolepsy is due a loss of hypocretin, as a result of depletion of hypocretin neurons. As such, it may be useful to consider ways to replace the loss [10].

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