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Human Molecular Genetics Advance Access published online on November 3, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi004
© 2004 by Oxford University Press
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Article

Orexin loss in Huntington's disease

Åsa Petersén 1*, Joana Gil 1, Marion LC Maat-Schieman 2, Maria Björkqvist 3, Heikki Tanila 4, Ines M Araújo 5, Ruben Smith 1, Natalija Popovic 1, Nils Wierup 6, Per Norlén 7, Jia-Yi Li 1, Raymund AC Roos 2, Frank Sundler 6, Hindrik Mulder 3, and Patrik Brundin 1

1 Department of Physiological Sciences, Section for Neuronal Survival, BMC A10, 221 84 Lund, Sweden
2 Department of Neurology, LUMC, Leiden, the Netherlands
3 Department of Cell and Molecular Biology, 221 84 Lund, Sweden
4 Department of Neuroscience and Neurology, University of Kuopio, Department of Neurology, Kuopio University Hospital, Finland
5 Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal
6 Department of Physiological Sciences, Section for Neuroendocrine and Cell Biology, BMC F10, 221 84 Lund, Sweden
7 Department of Experimental and Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden

* To whom correspondence should be addressed.
Åsa Petersén, E-mail: asa.petersen{at}mphy.lu.se


  Abstract

Huntington's disease 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 Huntington's disease 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 to wild-type littermates, suggesting that orexin could be used as a biomarker reflecting neurodegeneration. Our results show that loss of orexin is a novel and potentially very important pathology in Huntington's disease.


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