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Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain
Julia Lindberg1, Peter Saetre, Seiji Nishino
1Evolutionary Biology Centre, Department of Evolution, Genomics and Systematics, Uppsala University, Norbyvägen 18D, Uppsala, Sweden. julia.lindberg@ebc.uu.se <julia.lindberg@ebc.uu.se>
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.
Conclusion:
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.
Insights
Narcolepsy in dogs is linked to reduced expression of Tachykinin precursor 1 (TAC1), Proenkephalin (PENK), and Suppressor of cytokine signaling 2 (SOCS2). These genes may play a role in excessive daytime sleepiness across species.
Area of Science:
- Neuroscience
- Genetics
Background:
- Narcolepsy is characterized by excessive sleepiness and cataplexy, linked to hypocretin system deficiencies.
- Studies in humans and dogs implicate hypocretin ligand (HCRT) absence or hypocretin receptor 2 (HCRTR2) mutations.
- Molecular changes downstream of hypocretin signaling remain largely unknown.
Purpose of the Study:
- To investigate gene expression alterations in the brains of Doberman dogs with heritable narcolepsy.
- To identify molecular pathways affected by the HCRTR2-2 mutation.
Main Methods:
- Microarray analysis of 29,760 genes in narcoleptic Doberman dogs and unaffected siblings.
- Real-time RT-PCR to confirm microarray findings.
Main Results:
- Reduced expression of Tachykinin precursor 1 (TAC1), Proenkephalin (PENK), and Suppressor of cytokine signaling 2 (SOCS2) in narcoleptic dog brains.
- Significant downregulation of PENK (6.2-fold), TAC1 (4.4-fold), and SOCS2 (2.8-fold) observed in the amygdala.
- Expression changes were confirmed via real-time RT-PCR.
Conclusions:
- TAC1, PENK, and SOCS2 are potentially involved in the pathophysiology of narcolepsy.
- These findings suggest a conserved molecular mechanism for excessive daytime sleepiness across species, including humans.
