title: Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat.
abstract: The sleep disorder narcolepsy has been linked to loss of hypothalamic neurons producing the orexin (hypocretin) neuropeptides. Here, we report the generation of transgenic rats expressing a human ataxin-3 fragment with an elongated polyglutamyl stretch under control of the human prepro-orexin promoter (orexin/ataxin-3 rats). At 17 weeks of age, the transgenic rats exhibited postnatal loss of orexin-positive neurons in the lateral hypothalamus, and orexin-containing projections were essentially undetectable. The loss of orexin production resulted in the expression of a phenotype with fragmented vigilance states, a decreased latency to rapid eye movement (REM) sleep and increased REM sleep time during the dark active phase. Wakefulness time was also reduced during the dark phase, and this effect was concentrated at the photoperiod boundaries. Direct transitions from wakefulness to REM sleep, a defining characteristic of narcolepsy, occurred frequently. Brief episodes of muscle atonia and postural collapse resembling cataplexy were also noted while rats maintained the electroencephalographic characteristics of wakefulness. These findings indicate that the orexin/ataxin-3 transgenic rat could provide a useful model of human narcolepsy.
authors.affiliation: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA.
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Beuckmann
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sinton
authors.forename: S Clay
authors.initials: SC
authors.lastname: Williams
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001143:Arousal / Q000235:genetics; D000067699:Ataxin-3; D001522:Behavior, Animal / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004576:Electromyography; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009290:Narcolepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000172:deficiency / Q000378:metabolism*; D009687:Nuclear Proteins; D000068797:Orexins; D010641:Phenotype; D017440:Photoperiod; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins; D012895:Sleep, REM / Q000235:genetics; D019076:Transgenes; D014851:Wakefulness / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511593:Atxn3 protein, rat