title: Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.
abstract: BACKGROUND
  Narcolepsy 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.
  
  
  RESULTS
  By 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Evolutionary Biology Centre, Department of Evolution, Genomics and Systematics, Uppsala University, Norbyvägen 18D, Uppsala, Sweden. julia.lindberg@ebc.uu.se <julia.lindberg@ebc.uu.se>
authors.forename: Julia
authors.initials: J
authors.lastname: Lindberg
authors.forename: Peter
authors.initials: P
authors.lastname: Saetre
authors.forename: Seiji
authors.initials: S
authors.lastname: Nishino
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
authors.forename: Elena
authors.initials: E
authors.lastname: Jazin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D015536:Down-Regulation; D004745:Enkephalins / Q000378:metabolism*; D009154:Mutation; D009290:Narcolepsy / Q000378:metabolism*; D064446:Orexin Receptors; D011498:Protein Precursors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D015320:Tachykinins / Q000378:metabolism*
chemical_list: D004745:Enkephalins; D064446:Orexin Receptors; D011498:Protein Precursors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D015320:Tachykinins; C029992:proenkephalin; C054618:protachykinin