The orexin system (also known as hypocretin system) is a critical neuropeptide signaling network that plays a central role in regulating arousal, wakefulness, sleep-wake transitions, and various other physiological functions. Comprising orexin-A and orexin-B neuropeptides (also called hypocretin-1 and hypocretin-2), this system acts through two G-protein-coupled receptors (OX1R and OX2R) to maintain wakefulness and regulate energy homeostasis[@sakurai2007]. Emerging evidence demonstrates that orexin dysfunction contributes significantly to the pathogenesis of neurodegenerative diseases, particularly through its effects on sleep disruption, [circadian rhythm](/mechanisms/circadian-rhythm-neurodegeneration) disturbances, and cellular homeostasis[@thompson2022]. The orexin system has emerged as a promising therapeutic target for addressing sleep disorders in [Alzheimer's disease](/diseases/alzheimers-disease) (AD), [Parkinson's disease](/diseases/parkinsons-disease) (PD), and [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) (ALS), with potential disease-modifying implications[@ferr2023].
The orexin system (also known as hypocretin system) is a critical neuropeptide signaling network that plays a central role in regulating arousal, wakefulness, sleep-wake transitions, and various other physiological functions. Comprising orexin-A and orexin-B neuropeptides (also called hypocretin-1 and hypocretin-2), this system acts through two G-protein-coupled receptors (OX1R and OX2R) to maintain wakefulness and regulate energy homeostasis[@sakurai2007]. Emerging evidence demonstrates that orexin dysfunction contributes significantly to the pathogenesis of neurodegenerative diseases, particularly through its effects on sleep disruption, [circadian rhythm](/mechanisms/circadian-rhythm-neurodegeneration) disturbances, and cellular homeostasis[@thompson2022]. The orexin system has emerged as a promising therapeutic target for addressing sleep disorders in [Alzheimer's disease](/diseases/alzheimers-disease) (AD), [Parkinson's disease](/diseases/parkinsons-disease) (PD), and [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) (ALS), with potential disease-modifying implications[@ferr2023].
The orexin system consists of two related but distinct neuropeptides derived from a single precursor peptide, prepro-orexin, encoded by the [HCRT](/entities/hcrt-gene) gene located on chromosome 17q21[@de1998]. Orexin-A (33 amino acids) and orexin-B (28 amino acids) are produced in neurons located primarily in the lateral hypothalamus, perifornical area, and dorsomedial hypothalamus[@peyron1998]. These neurons project widely throughout the brain, including to the basal forebrain, cortex, locus coeruleus, dorsal raphe, and tuberomammillary nucleus, establishing orexin as a central coordinator of arousal states[@saper2010].
Two orexin receptors mediate the effects of orexin neuropeptides: orexin receptor 1 (OX1R/HCXR1) and orexin receptor 2 (OX2R/HCXR2)[@marcus2001]. OX1R has higher affinity for orexin-A, while OX2R binds both orexin-A and orexin-B with similar affinity[@smart2000]. The distribution of these receptors in the brain differs significantly: OX1R is predominantly expressed in the locus coeruleus, hippocampus, and cortex, while OX2R is more abundant in the histaminergic tuberomammillary nucleus and paraventricular nucleus[@trivedi1998]. This differential distribution underlies the distinct roles of orexin signaling in various physiological processes[@mieda2009].
Orexin-producing neurons form extensive projections throughout the central nervous system, creating a broad network that influences multiple brain regions[@yoshida2001]. The ascending orexinergic projections innervate the basal forebrain cholinergic system and cortex, promoting cortical activation and wakefulness[@jones2005]. Descending projections to brainstem nuclei, including the locus coeruleus (noradrenergic), dorsal raphe (serotonergic), and laterodorsal tegmental nucleus (cholinergic), coordinate state transitions and maintain arousal[@saper2001].
The orexin system maintains reciprocal connections with the suprachiasmatic nucleus (SCN), the central circadian clock, integrating circadian and homeostatic sleep drive[@astonjones2001]. This relationship is particularly relevant to neurodegenerative diseases, where circadian rhythm disturbances are common early symptoms[@videnovic2013]. Additionally, orexin neurons receive input from the retina (via the intergeniculate leaflet), providing a pathway for light-mediated regulation of sleep-wake cycles[@moore2007].
Orexin neurons are maximally active during active wakefulness, particularly during periods of motor activity, exploration, and motivated behavior[@lee2005]. The orexin system's role in maintaining wakefulness is primarily mediated through excitation of wake-promoting neurotransmitters, including acetylcholine, norepinephrine, serotonin, and histamine[@espana2011]. Studies in orexin-deficient mice demonstrate that loss of orexin signaling produces narcolepsy-like symptoms, including sudden sleep onset and cataplexy, establishing orexin as essential for sleep-wake stability[@chemelli1999].
The orexin system also regulates the switch between non-rapid eye movement (NREM) and REM sleep, with orexin neurons being silent during REM sleep[@lee2005a]. This gating function is disrupted in narcolepsy and may contribute to sleep fragmentation observed in neurodegenerative diseases[@saper2010a]. Furthermore, orexin influences the timing and architecture of sleep through interactions with the circadian clock and homeostatic sleep pressure systems[@jones2005a].
Beyond sleep-wake regulation, orexin neurons integrate metabolic and nutritional signals to coordinate behavior with energy status[@sakurai2007a]. Orexin neurons respond to circulating glucose, leptin, ghrelin, and other metabolic hormones, modulating feeding behavior, energy expenditure, and locomotor activity[@yamanaka2003]. This metabolic coupling is relevant to neurodegenerative diseases, where metabolic dysfunction is a common feature[@cai2022]. In PD and AD, altered orexin signaling may contribute to weight changes and metabolic disturbances observed in patients[@lill2012].
Sleep disturbances are among the earliest and most prevalent symptoms in AD, often preceding cognitive decline by years or even decades[@brzecka2018]. Clinical studies demonstrate reduced cerebrospinal fluid (CSF) orexin-A levels in AD patients compared to healthy controls, suggesting orexin system dysfunction[@guldbrandsen2014]. However, other studies report elevated orexin-A in early AD, potentially reflecting compensatory mechanisms or sleep fragmentation-related increases[@liguori2014]. The relationship between orexin and AD appears complex and may vary with disease stage.
Polysomnographic studies reveal significant sleep architecture abnormalities in AD patients, including reduced sleep efficiency, increased wake after sleep onset (WASO), decreased REM sleep, and increased NREM sleep fragmentation[@bliwise2004]. These disturbances correlate with amyloid burden and cognitive impairment severity, suggesting bidirectional relationships between sleep disruption and AD pathophysiology[@ju2013]. Orexin antagonists have shown promise in improving sleep quality in AD patients, though effects on disease progression remain unclear[@herring2020].
The orexin system interacts with AD pathophysiology through multiple mechanisms[@zhou2021]. [Amyloid-beta](/proteins/amyloid-beta-protein) (Aβ) pathology may directly or indirectly affect orexin neurons in the lateral hypothalamus[@roh2014]. Studies in APP/PS1 transgenic mice demonstrate increased orexin neuron loss and reduced orexin-A levels in the hypothalamus, correlating with sleep disturbances[@zhang2020]. Conversely, orexin administration in animal models promotes Aβ production through cAMP/PKA signaling, potentially creating a vicious cycle[@kang2009].
[Tau pathology](/mechanisms/tau-pathology) also affects orexin signaling in AD[@grunstein2022]. Postmortem studies reveal tau accumulation in orexin neurons in AD patients, which may disrupt their function and contribute to sleep-wake abnormalities[@van2020]. The glymphatic system, which clears metabolic waste including Aβ and tau during sleep, is regulated by orexin, suggesting that orexin dysfunction may impair this clearance mechanism[@xie2013]. Sleep deprivation enhances tau propagation in mouse models, an effect that may be mediated through orexin signaling[@holth2019].
Targeting the orexin system offers therapeutic opportunities in AD[@ferr2023a]. Dual orexin receptor antagonists (DORAs), such as suvorexant and lemborexant, are approved for insomnia treatment and have shown potential for improving sleep in AD[@herring2020a]. However, concerns exist about whether enhancing sleep (and potentially reducing glymphatic clearance) might have unintended consequences[@nedergaard2020]. Alternatively, orexin agonists could potentially restore orexin signaling in early AD, though no such compounds are currently approved[@smith2021].
Sleep disorders are extremely common in PD, affecting up to 90% of patients and significantly impacting quality of life[@suzuki2017]. Rapid eye movement sleep behavior disorder (RBD), insomnia, excessive daytime sleepiness (EDS), and sleep fragmentation are among the most prevalent sleep disturbances[@videnovic2014]. Notably, RBD often precedes motor symptoms of PD by years or decades, suggesting early involvement of brainstem sleep-wake regulatory systems[@dauvilliers2020].
Studies of orexin in PD have yielded mixed results[@friess2004]. Some studies report reduced CSF orexin-A levels in PD patients, particularly those with EDS, while others find no significant differences[@compta2015]. Postmortem studies reveal reduced orexin neuron numbers in the lateral hypothalamus of PD patients, similar to findings in AD[@thannickal2007]. The loss of orexin neurons correlates with disease duration and severity, suggesting progressive involvement[@feng2020].
The orexin system may contribute to PD pathogenesis through multiple pathways[@zhou2021a]. [Alpha-synuclein](/proteins/alpha-synuclein) pathology can affect orexin neurons directly, as Lewy bodies have been identified in the hypothalamus of PD patients[@braak2003]. Sleep disruption in PD may also result from dysfunction in brainstem nuclei that regulate REM sleep, including the sublaterodorsal nucleus and pedunculopontine nucleus, which receive orexinergic input[@saper2010b].
[Mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction-parkinsons), a central feature of PD pathogenesis, may also affect orexin neurons[@surmeier2017]. Studies demonstrate that orexin neurons are particularly vulnerable to mitochondrial toxins and genetic PD risk factors[@gonzalezrodriguez2021]. The relationship between orexin and PD may also involve [neuroinflammation](/mechanisms/neuroinflammation), as orexin has anti-inflammatory properties that could be protective[@garland2022].
Orexin-based therapies for PD sleep disorders are under investigation[@videnovic2016]. Suvorexant has been studied in PD patients with insomnia, showing improvements in sleep parameters without significant adverse effects[@liguori2020]. Additionally, orexin receptor agonists may potentially protect orexin neurons or restore function in PD[@smith2021a]. Given the bidirectional relationship between sleep and PD progression, addressing orexin dysfunction may have disease-modifying potential[@videnovic2013a].
Sleep disturbances are common in ALS and significantly impact quality of life, respiratory function, and survival[@lo2017]. Insomnia, sleep fragmentation, and sleep-disordered breathing are frequently reported[@atalaia2020]. Notably, some studies suggest that orexin system dysfunction may be more pronounced in ALS compared to other neurodegenerative diseases[@overeem2004]. CSF orexin-A levels have been reported to be reduced in ALS patients, correlating with disease severity and respiratory function[@takahashi2013].
The pathophysiology of orexin dysfunction in ALS likely involves multiple mechanisms[@vanacore2021]. [Motor neuron](/cell-types/motor-neurons-als) degeneration may affect descending inputs to orexin neurons, disrupting their regulation[@choudhry2022]. Additionally, [TDP-43 pathology](/mechanisms/als-tdp43-pathology), the hallmark protein aggregate in ALS, can affect hypothalamic regions including orexin neuron populations[@neumann2009]. Sleep-disordered breathing, particularly obstructive sleep apnea, is highly prevalent in ALS and may contribute to orexin system dysfunction through intermittent hypoxia[@boentert2020].
Targeting orexin in ALS presents both opportunities and challenges[@smith2021b]. Improving sleep quality may enhance respiratory function and potentially slow disease progression[@videnovic2013b]. However, the role of orexin in motor neuron function is complex, and further research is needed to understand the optimal therapeutic approach[@ferr2023b].
Orexin has demonstrated anti-inflammatory properties in various experimental models[@garland2022a]. Orexin-A administration reduces pro-inflammatory cytokine production (IL-1β, TNF-α, IL-6) in the brain and peripheral [immune cells](/cell-types/immune-cells-neurodegeneration)[@xi2019]. These effects are mediated through OX1R and OX2R signaling, including modulation of NF-κB and [MAPK pathways](/mechanisms/erk-mapk-signaling-neurodegeneration)[@yuan2011]. Given the central role of neuroinflammation in neurodegenerative disease pathogenesis, orexin's anti-inflammatory effects may contribute to neuroprotection[@zhou2021b].
Orexin receptors are expressed on [microglia](/cell-types/microglia-neurodegeneration) and [astrocytes](/cell-types/astrocytes-neurodegeneration), allowing direct modulation of glial function[@sirri2019]. Orexin-A promotes microglial polarization toward an anti-inflammatory (M2-like) phenotype and enhances astrocyte neuroprotective functions[@backberg2004]. In neurodegenerative disease contexts, orexin may therefore reduce glial-mediated [neuroinflammation](/mechanisms/neuroinflammation) and support neuronal survival[@ferr2023c].
Dual orexin receptor antagonists (DORAs) are approved for insomnia treatment and have been studied in neurodegenerative diseases[@krystal2019]. Suvorexant (Belsomra), lemborexant (Dayvigo), and daridorexant (Quviviq) represent the current therapeutic options[@hoyer2013]. These compounds promote sleep by blocking orexin signaling, potentially addressing sleep disturbances in AD, PD, and ALS[@herring2020b]. Clinical trials in neurodegenerative disease populations are ongoing[@ferr2023d].
Conversely, orexin receptor agonists could potentially restore orexin signaling in diseases where orexin deficiency is observed[@smith2021c]. Such compounds are under development for narcolepsy but could potentially be repurposed for neurodegenerative diseases[@nagahara2015]. Challenges include achieving appropriate receptor selectivity and brain penetration[@gotter2012].
Non-pharmacological approaches targeting the orexin system include sleep hygiene optimization, light therapy, and exercise[@walker2017]. These interventions can help normalize circadian rhythms and potentially improve orexin function[@terman2005]. Morning light exposure, in particular, can strengthen circadian amplitude and improve sleep-wake stability[@czeisler1999].
Orexin levels in CSF, blood, and other tissues may serve as biomarkers for neurodegenerative disease diagnosis or progression[@dauvilliers2020a]. However, standardization of assays and larger validation studies are needed[@saper2021]. The relationship between orexin and disease-specific pathologies (Aβ, tau, α-synuclein, TDP-43) requires further investigation[@zhou2021c].
Whether targeting the orexin system can modify neurodegenerative disease progression remains an open question[@ju2013a]. The bidirectional relationships between sleep and protein aggregation suggest that improving sleep could potentially slow pathology spread[@nedergaard2020a]. However, this hypothesis requires testing in long-term clinical trials[@ferr2023e].
Individual variations in orexin system function may influence disease presentation and treatment responses[@shi2022]. Precision medicine approaches that account for orexin status may optimize therapeutic outcomes[@videnovic2023]. Future studies should examine orexin genetics, biomarker levels, and treatment responses to develop personalized interventions[@ferr2024].
The orexin/hypocretin system represents a critical node connecting sleep-wake regulation, metabolism, and neurodegeneration. Dysfunction of this system contributes to the sleep disturbances that characterize AD, PD, and ALS, potentially through both direct neuropathological effects and secondary consequences of protein aggregation and neuronal loss. Therapeutic targeting of orexin receptors offers promise for improving sleep and possibly modifying disease progression in neurodegenerative conditions. Further research is needed to clarify the complex relationships between orexin signaling and disease-specific pathophysiology, ultimately leading to effective orexin-based interventions for patients.