Hypocretin levels in sporadic and familial cases of canine narcolepsy.
Familial and sporadic forms of narcolepsy exist in both humans and canines. Mutations in the hypocretin receptor 2 gene (Hcrtr 2) cause canine familial narcolepsy. In humans, mutations in hypocretin-related genes are rare, but cerebrospinal fluid (CSF) hypocretin-1 is undetectable in most sporadic cases. Using the canine model, we investigated ( 1 ) whether hypocretin deficiency is involved in sporadic cases and ( 2 ) whether alterations in hypocretin neurons or ligand levels also contribute to the phenotype in Hcrtr 2 mutants. We found that hypocretins were undetectable in the brains of three of three and the CSF of two of two sporadic narcoleptic dogs tested. In contrast, hypocretin levels were not altered in brains and CSF of genetically narcoleptic Dobermans, and hypocretin-containing neurons were of normal appearance. Therefore, multiple hypocretin-related etiologies are likely to be involved in canine narcolepsy. The presence of hypocretin peptides in Hcrtr 2-mutated animals suggests that neurotransmission through Hcrtr 1 may be intact, arguing for a preferential importance of Hcrtr 2-mediated function in narcolepsy.
Ripley
B
B
Center for Narcolepsy, Stanford Sleep Center, Stanford University School of Medicine, Palo Alto, California 94304, USA.
Fujiki
N
N
Okura
M
M
Mignot
E
E
Nishino
S
S
D000367:Age Factors; D000818:Animals; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000032:analysis / Q000097:blood / Q000134:cerebrospinal fluid*; D004285:Dogs; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D009290:Narcolepsy / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics; D009474:Neurons / Q000737:chemistry; D009479:Neuropeptides / Q000032:analysis / Q000097:blood / Q000134:cerebrospinal fluid*; D000068797:Orexins; D011863:Radioimmunoassay
D002352:Carrier Proteins; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins