Abstract
BackgroundNarcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. 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). However, little is known about molecular alterations downstream of the hypocretin signals.ResultsBy 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 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. 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. 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. The results obtained from microarray experiments were confirmed by real-time RT-PCR. 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.ConclusionThese 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.
Highlights
Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli
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
Microarray analysis To assess whether brain gene expression differed between narcoleptic and heterozygous dogs, we compared the relative messenger RNA (mRNA) levels in pools of narcoleptic and heterozygous siblings in three regions of the brain, using eight complementary DNA (cDNA) microarrays
Summary
Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Linkage analysis and subsequent positional cloning experiments identified the canarc-1 to be hypocretin receptor 2 (HCRTR2) [7] This finding was rapidly followed by findings in human narcolepsy where hypocretin ligand deficiency was found in most narcolepsy-cataplexy cases [8,9]. 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 knowledge will be essential to link the alterations in dogs with possible alterations in humans that lead to similar symptoms. Since all animals were raised in the same environmental conditions and have a very similar genetic background, our experiment offers a unique opportunity to identify molecular pathways that have been altered in narcolepsy in the absence of large environmental variables that modify mRNA expression levels
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