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Human Molecular Genetics Advance Access originally published online on November 3, 2004
Human Molecular Genetics 2005 14(1):39-47; doi:10.1093/hmg/ddi004
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved

Orexin loss in Huntington's disease

Åsa Petersén1,*,{dagger}, Joana Gil1,{dagger}, Marion L.C. Maat-Schieman2, Maria Björkqvist3, Heikki Tanila4, Inês M. Araújo5, Ruben Smith1, Natalija Popovic1, Nils Wierup6, Per Norlén7, Jia-Yi Li1, Raymund A.C. Roos2, Frank Sundler6, Hindrik Mulder3 and Patrik Brundin1

1Department of Physiological Sciences, Section for Neuronal Survival, BMC A10, 22184 Lund, Sweden, 2Department of Neurology, LUMC, Leiden, The Netherlands, 3Department of Cell and Molecular Biology, Lund, Sweden, 4Department of Neuroscience and Neurology, University of Kuopio/Department of Neurology, Kuopio University Hospital, Finland, 5Center for Neuroscience and Cell Biology, Department of Zoology, Coimbra, Portugal, 6Department of Physiological Sciences, Section for Neuroendocrine Cell Biology, Lund, Sweden and 7Department of Experimental and Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden

* To whom correspondence should be addressed. Tel: +46 462220525; Fax: +46 462220531; Email: asa.petersen{at}mphy.lu.se

Received September 26, 2004; Accepted October 22, 2004

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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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