Journal Article

Orexin loss in Huntington's disease

Åsa Petersén, Joana Gil, Marion L.C. Maat-Schieman, Maria Björkqvist, Heikki Tanila, Inês M. Araújo, Ruben Smith, Natalija Popovic, Nils Wierup, Per Norlén, Jia-Yi Li, Raymund A.C. Roos, Frank Sundler, Hindrik Mulder and Patrik Brundin

in Human Molecular Genetics

Volume 14, issue 1, pages 39-47
Published in print January 2005 | ISSN: 0964-6906
Published online November 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi004
Orexin loss in Huntington's disease

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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.

Journal Article.  6059 words.  Illustrated.

Subjects: Genetics and Genomics

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