The neurobiological basis of narcolepsy

Mahoney, Carrie E.; Cogswell, Andrew; Koralnik, Igor J.; Scammell, Thomas E.

doi:10.1038/s41583-018-0097-x

Cited by 167 publications

(147 citation statements)

References 202 publications

(187 reference statements)

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“…Repeated OrxR inhibition may cause nonspecific side effects by influencing numerous neural pathways. Dysfunctions of the Orx system can cause narcolepsy [65][66][67], while pharmacological manipulations of the Orx system can have nonspecific side effects on food intake [68][69][70], inhibitory responses [71][72][73], and learning and memory [74][75][76]. Such untoward effects need to be considered when investigating the clinical potential of OrxR antagonist treatment.…”

Section: The Orexin System and Substance Use Disordermentioning

confidence: 99%

Targeting the Orexin System for Prescription Opioid Use Disorder

Matzeu

Martin‐Fardon

2020

Brain Sciences

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Prescription opioids are potent analgesics that are used for clinical pain management. However, the nonmedical use of these medications has emerged as a major concern because of dramatic increases in abuse and overdose. Therefore, effective strategies to prevent prescription opioid use disorder are urgently needed. The orexin system has been implicated in the regulation of motivation, arousal, and stress, making this system a promising target for the treatment of substance use disorder. This review discusses recent preclinical studies that suggest that orexin receptor blockade could be beneficial for the treatment of prescription opioid use disorder.

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Section: The Orexin System and Substance Use Disordermentioning

confidence: 99%

Targeting the Orexin System for Prescription Opioid Use Disorder

Matzeu

Martin‐Fardon

2020

Brain Sciences

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“…The two types of orexins and receptors appear to have a partly overlapping and partly distinct function (22). Besides orexins, the orexinproducing neurons also release other neuromodulators, such as glutamate, dynorphin, and neuronal activity-regulated pentraxin (NARP) (23)(24)(25).…”

Section: The Orexin System: An Overviewmentioning

confidence: 99%

“…However, none of the currently existing models adequately and precisely reflect the human situation. As mentioned above, in patients with narcolepsy type 1, orexinproducing neurons are lost, resulting in the loss of orexin but also of the co-expressed glutamate, dynorphin, and NARP (25). Therefore, mouse models that mimic narcolepsy type 1 by means of inhibition of the OXR or a lack of preproorexin might not be fully adequate.…”

Section: Human Perspectivementioning

confidence: 99%

Role of Brown Adipose Tissue in Adiposity Associated With Narcolepsy Type 1

et al. 2020

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Narcolepsy type 1 is a neurological sleep-wake disorder caused by the destruction of orexin (hypocretin)-producing neurons. These neurons are particularly located in the lateral hypothalamus and have widespread projections throughout the brain, where they are involved, e.g., in the regulation of the sleep-wake cycle and appetite. Interestingly, a higher prevalence of obesity has been reported in patients with narcolepsy type 1 compared to healthy controls, despite a normal to decreased food intake and comparable physical activity. This suggests the involvement of tissues implicated in total energy expenditure, including skeletal muscle, liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Recent evidence from pre-clinical studies with orexin knockout mice demonstrates a crucial role for the orexin system in the functionality of brown adipose tissue (BAT), probably through multiple pathways. Since BAT is a highly metabolically active organ that combusts fatty acids and glucose toward heat, thereby contributing to energy metabolism, this raises the question of whether BAT plays a role in the development of obesity and related metabolic diseases in narcolepsy type 1. BAT is densely innervated by the sympathetic nervous system that activates BAT, for instance, following cold exposure. The sympathetic outflow toward BAT is mainly mediated by the dorsomedial, ventromedial, arcuate, and paraventricular nuclei in the hypothalamus. This review focuses on the current knowledge on the role of the orexin system in the control of energy balance, with specific focus on BAT metabolism and adiposity in both preclinical and clinical studies.

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“…Other human sleep disorders that involve hypersomnolence [but no narcolepsy (106)] occur in 1 out of ∼10,000 births and are referred to as idiopathic (cause unknown) conditions (https://www. orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=33208).…”

Section: Hypersomnolence Of Patients With Calpain-activating Wolframmentioning

confidence: 99%

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

Varshavsky

2019

Proc. Natl. Acad. Sci. U.S.A.

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The molecular-level cause of sleep is unknown. In 2012, we suggested that the cause of sleep stems from cumulative effects of numerous intracellular and extracellular protein fragments. According to the fragment generation (FG) hypothesis, protein fragments (which are continually produced through nonprocessive cleavages by intracellular, intramembrane, and extracellular proteases) can be beneficial but toxic as well, and some fragments are eliminated slowly during wakefulness. We consider the FG hypothesis and propose that, during wakefulness, the degradation of accumulating fragments is delayed within natural protein aggregates such as postsynaptic densities (PSDs) in excitatory synapses and in other dense protein meshworks, owing to an impeded diffusion of the ∼3,000-kDa 26S proteasome. We also propose that a major function of sleep involves a partial and reversible expansion of PSDs, allowing an accelerated destruction of PSD-localized fragments by the ubiquitin/proteasome system. Expansion of PSDs would alter electrochemistry of synapses, thereby contributing to a decreased neuronal firing during sleep. If so, the loss of consciousness, a feature of sleep, would be the consequence of molecular processes (expansions of protein meshworks) that are required for degradation of protein fragments. We consider the concept of FG sentinels, which signal to sleep-regulating circuits that the levels of fragments are going up. Also discussed is the possibility that protein fragments, which are known to be overproduced during an epileptic seizure, may contribute to postictal sleep and termination of seizures. These and related suggestions, described in the paper, are compatible with current evidence about sleep and lead to testable predictions. fragment | extracellular | intracellular | proteolysis | sleep S leep is universal among mammals and other vertebrates.Animals with much smaller nervous systems, such as insects, also sleep (1-8). Mechanisms that control sleep include circadian circuits, which underlie daily rhythms of sleep and other biological variables (9). However, circadian aspects of sleep do not define it entirely, because sleep has the homeostatic property of becoming longer after sleep deprivation (10, 11). In mammals, birds, and lizards, two alternating modes of sleep have been identified, the non-rapid eye movement (NREM) sleep and the rapid eye movement (REM) sleep (12,13). The depth of NREM sleep is yet another sleep variable. In adult humans, NREM sleep occupies ∼80% of the total sleep time. For recent reviews of sleep, see refs. 14-20.Despite advances in the understanding of neuronal circuits as well as genes, proteins, short peptides, and other compounds that regulate sleep, it is largely unknown why sleep exists and what it is for. Maladaptive aspects of sleep include elevated dangers of predation during sleep, the neglect of territorial defense and foraging for food, and the loss of parental care and mating opportunities. It is unknown what features of sleep did not allow these fitness costs to ca...

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The neurobiological basis of narcolepsy

Cited by 167 publications

References 202 publications

Targeting the Orexin System for Prescription Opioid Use Disorder

Targeting the Orexin System for Prescription Opioid Use Disorder

Role of Brown Adipose Tissue in Adiposity Associated With Narcolepsy Type 1

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

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