![]() Impairment in the hypocretin system is well established as the origin of the condition, but little is known about the downstream molecular alterations that may lead to the phenotypes related to narcolepsy. This finding was rapidly followed by findings in human narcolepsy where hypocretin ligand deficiency was found in most narcolepsy-cataplexy cases. Linkage analysis and subsequent positional cloning experiments identified the canarc-1 to be hypocretin receptor 2 ( HCRTR2). Homozygous individuals show several symptoms similar to the human form of narcolepsy including emotionally triggered cataplexy (sudden loss of muscle tone), short sleep latency and fragmented sleep. The genetic transmission of the mutation, also known as canarc-1, is autosomal recessive. A colony of Doberman pinschers with a heritable form of narcolepsy due to a mutation in a single major gene was established at Stanford Sleep Research Center in 1976. Canine narcolepsy was first reported in the 1970's, and since then dogs have been extensively used for exploring the underlying mechanisms of the disease. The human form of narcolepsy is caused by an interplay of genetic and environmental factors and appear mostly in sporadic cases. Narcolepsy is a sleep disorder found in several mammal species. These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice. The results obtained from microarray experiments were confirmed by real-time RT-PCR. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 ( TAC1) and Proenkephalin ( PENK), that together with Suppressor of cytokine signaling 2 ( SOCS2), showed reduced expression in narcoleptic brains. Resultsīy using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 mutation), and their unaffected heterozygous siblings. However, little is known about molecular alterations downstream of the hypocretin signals. Deficiencies in the hypocretin system are well established as the origin of the condition both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 ( HCRTR2). ![]() Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli.
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