Petersén Asa, Gil Joana, Maat-Schieman Marion L C, Björkqvist Maria, Tanila Heikki, Araújo Inês M, Smith Ruben, Popovic Natalija, Wierup Nils, Norlén Per, Li Jia-Yi, Roos Raymund A C, Sundler Frank, Mulder Hindrik, Brundin Patrik
Department of Physiological Sciences, Section for Neuronal Survival, Lund, Sweden.
Hum Mol Genet. 2005 Jan 1;14(1):39-47. doi: 10.1093/hmg/ddi004. Epub 2004 Nov 3.
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.
亨廷顿舞蹈症（HD）是一种由编码亨廷顿蛋白（一种功能未知的蛋白质）的基因中CAG重复序列扩增引起的毁灭性神经退行性疾病。突变的亨廷顿蛋白形成细胞内聚集体，并与特定脑区的神经元死亡有关。研究最多的HD小鼠模型（R6/2）复制了该疾病的许多特征，但据报道仅表现出极少的神经元死亡。我们首次描述了R6/2小鼠下丘脑外侧区食欲素神经元的显著萎缩和丧失。重要的是，我们还在亨廷顿病患者中发现了食欲素神经元的显著萎缩和丧失。与动物模型及食欲素功能受损的患者一样，R6/2小鼠患有发作性睡病。与野生型同窝小鼠相比，晚期R6/2小鼠下丘脑外侧区食欲素神经元数量和脑脊液中食欲素水平均降低了72%，这表明食欲素可用作反映神经退行性变的生物标志物。我们的结果表明，食欲素丧失是HD中一种新的且可能非常重要的病理变化。
