title: Orexin loss in Huntington's disease.
abstract: Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin, a protein of unknown function. Mutant huntingtin forms intracellular aggregates and is associated with neuronal death in select brain regions. The most studied mouse model (R6/2) of HD replicates many features of the disease, but has been reported to exhibit only very little neuronal death. We describe for the first time a dramatic atrophy and loss of orexin neurons in the lateral hypothalamus of R6/2 mice. Importantly, we also found a significant atrophy and loss of orexin neurons in Huntington patients. Like animal models and patients with impaired orexin function, the R6/2 mice were narcoleptic. Both the number of orexin neurons in the lateral hypothalamus and the levels of orexin in the cerebrospinal fluid were reduced by 72% in end-stage R6/2 mice compared with wild-type littermates, suggesting that orexin could be used as a biomarker reflecting neurodegeneration. Our results show that the loss of orexin is a novel and potentially very important pathology in HD.
authors.affiliation: Department of Physiological Sciences, Section for Neuronal Survival, Lund, Sweden. asa.petersen@mphy.lu.se
authors.forename: Asa
authors.initials: A
authors.lastname: Petersén
authors.forename: Joana
authors.initials: J
authors.lastname: Gil
authors.forename: Marion L C
authors.initials: ML
authors.lastname: Maat-Schieman
authors.forename: Maria
authors.initials: M
authors.lastname: Björkqvist
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Inês M
authors.initials: IM
authors.lastname: Araújo
authors.forename: Ruben
authors.initials: R
authors.lastname: Smith
authors.forename: Natalija
authors.initials: N
authors.lastname: Popovic
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.forename: Per
authors.initials: P
authors.lastname: Norlén
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Li
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.forename: Frank
authors.initials: F
authors.lastname: Sundler
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007031:Hypothalamus / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000068797:Orexins; D018911:Trinucleotide Repeats / Q000235:genetics / Q000502:physiology
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins