Orexin loss in Huntington's disease.
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.
Petersén
Asa
A
Department of Physiological Sciences, Section for Neuronal Survival, Lund, Sweden. asa.petersen@mphy.lu.se
Gil
Joana
J
Maat-Schieman
Marion L C
ML
Björkqvist
Maria
M
Tanila
Heikki
H
Araújo
Inês M
IM
Smith
Ruben
R
Popovic
Natalija
N
Wierup
Nils
N
Norlén
Per
P
Li
Jia-Yi
JY
Roos
Raymund A C
RA
Sundler
Frank
F
Mulder
Hindrik
H
Brundin
Patrik
P
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
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