Hypocretin/orexin and narcolepsy: new basic and clinical insights

Abstract

Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in a large majority of narcolepsy with cataplexy.Hypocretin ligand deficiency in human narcolepsy is likely due to the postnatal cell death of hypocretin neurons. Although tight association between human leukocyte antigen (HLA) association and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proven. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO) related disorder. These findings likely have significant clinical relevance and for understanding the mechanisms of hypocretin cell death and choice of treatment option.These series of discoveries in humans lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid [CSF] hypocretin-1 levels for narcolepsy with cataplexy and narcolepsy due to medical condition). Since a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress.

How Might Circadian Rhythms Control Mood? Let Me Count the Ways...

“…Leptin and ghrelin both signal through orexin neurons in the brain which enhance wakefulness when stimulated by ghrelin and promote sleep when inhibited by leptin (60). In fact, narcolepsy, a condition where individuals experience sudden sleep bouts, is caused by a dysfunctional orexin system, linking regulation of feeding and sleep to a small population of hypothalamic neurons (61). CCK is more widely expressed throughout the brain and gut including high levels of expression in GABAergic interneurons of the prefrontal cortex, dopaminergic neurons of the VTA, and the shell of the SCN (62–64).…”

Clinical Role of Human Leukocyte Antigen in Health and Disease

“…Such 'trans-species susceptibility' is difficult to reconcile with HLA-restricted antigen presentation. Third, significant HLA allele-based associations have been observed in conditions that do not involve antigen recognition or any immune-based pathogenesis [29]. Finally, antigen presentation-based hypotheses cannot easily explain allele-dose impact on disease severity or offer a plausible explanation for allele-dose effects on concordance rates in monozygotic twins [30].…”

Hormones, hormonal agents, and neuropeptides involved in the neuroendocrine regulation of sleep in humans

“…140 Hypocretin deficiency is also found in symptomatic cases of narcolepsy and excessive daytime sleepiness with various neurological conditions such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome, and neuromyelitis optica related disorder. 141 These findings in humans have led to the establishment of a new diagnostic test of narcolepsy based on CSF hypocretin-1 levels.…”