Narcolepsy A Neurodegenerative Disease of the Hypocretin System?

that narcoleptic dogs have mutations in one of the hypoIn the 2⁄2 years since hypocretin (also called orexin) was cretin receptors, the hypocretin receptor 2 (orexin 2 refirst described (de Lecea et al., 1998; Sakurai et al., ceptor) (Lin et al., 1999). Although different mutations 1998), more than 120 papers on the peptide have already were found in each of two narcoleptic breeds of dogs, been published. A pair of current contributions to this Dobermans and Labradors, in each breed the mutation rapidly expanding literature adds a new dimension to was localized to the hypocretin receptor 2, rendering it our understanding of this new peptide neurotransmitter/ nonfunctional. Detection of this mutation culminated a neuromodulator. Although additional confirming work is 10 year search for a defective gene using positional required, these new findings suggest that narcolepsy, cloning. Parallel studies in hypocretin knockout mice a condition characterized by serious sleep disturbances, revealed a similar narcoleptic phenotype (Chemelli et may be due to selective neurodegeneration of the hypoal., 1999), indicating that loss of either the peptide or thalamic hypocretin system. This would raise a disease one of the two peptide receptors results in narcolepsy. that not too long ago could find itself on the couch of These findings became even more exciting and relevant psychoanalysis onto the stage of the more common when hypocretin was found in the cerebrospinal fluid of neurodegenerative diseases. eight normal humans but could not be detected in seven The hypocretins are two peptides, hypocretin 1 of nine narcoleptics (Nishino et al., 2000). (orexin-A) and hypocretin 2 (orexin-B), generated from Absence of Hypocretin Neurons a single preprohypocretin and synthesized by a small in Narcoleptic Brain number of neurons restricted to the lateral hypothalaNew data based on immunocytochemistry and in situ mus and perifornical area (de Lecea et al., 1998; Sakurai hybridization indicate that there is a substantially deet al., 1998). In contrast, hypocretin axons are found creased number of neurons producing hypocretin in the throughout the CNS, with innervation of the hypothalahypothalamus of human narcoleptics (Peyron et al., mus, locus coeruleus, raphe, midline thalamus, all levels 2000; Thannickal et al., 2000 [this issue of Neuron]). of spinal cord, sympathetic and parasympathetic cenThannickal et al. show that the number of hypocretin ters, and many other brain regions (Peyron et al., 1998; immunoreactive neurons is decreased by about 90% in van den Pol, 1999). Two G protein–coupled receptors four narcoleptic human brains. In parallel, Peyron et al. that respond to the hypocretins have been identified show an absence of hypocretin mRNA from the hypo(Sakurai et al., 1998). In parallel to the wide distribution of thalamus, and the loss of hypocretin 1 and 2 peptides axons, the two hypocretin receptors show a widespread from extrahypothalamic hypocretin target regions of six and heterogeneous pattern of expression throughout narcoleptic brains. Although each study is based on a the CNS (Trivedi et al., 1998). Hypocretin raises synaptic relatively small number of narcoleptic brain specimens, activity in neurons of the hypothalamus (de Lecea et al., and each lab had only a few brain regions available, the 1998) and locus coeruleus (Hagan et al., 1999; Horvath combined brain number of both studies is ten, with six et al., 1999). Hypocretin can act on postsynaptic receptotal hypothalami, although a possibility exists that one tors to increase cytosolic calcium and can act at presynor two brains might have been shared by both groups. aptic receptors on axon terminals to enhance release Both studies of narcoleptic brains report no decreased of glutamate and GABA (van den Pol et al., 1998). The number of neurons containing melanin-concentrating fact that hypocretin can enhance activity of either excithormone, a neuroactive peptide found in cells in the atory or inhibitory neurons suggests that the peptide same general perifornical hypothalamic region where could ultimately increase or decrease the activity of inhypocretin neurons normally exist. This finding suggests nervated brain circuits. a very selective absence of hypocretin neurons, rather Dysfunction of Hypocretin System than a general loss of neurons from the hypothalamus. Causes Narcolepsy The absence of hypocretin neurons could be due to a Narcolepsy is a sleep disorder characterized by excesnumber of factors, including degeneration of hypocretin sive daytime sleepiness and unusual patterns of REM neurons, failure of hypocretin neurons to develop, a resleep. Narcolepsy is often associated with cataplexy, a duced synthesis or release of the peptide, or some mutasudden loss of muscle tone evoked by strong emotion. tion in the DNA sequence coding for hypocretin. SevDuring attacks of cataplexy that last a few seconds or eral lines of evidence support the hypothesis that minutes, narcoleptics are conscious of their environhypocretin neurons may degenerate in narcoleptics. ment but unable to move. This condition appears to be Thannickal et al. find about 10% of the normal number related to muscle atonia that occurs during REM sleep. of hypocretin neurons in narcoleptics, suggesting that