Green Edward W, Campesan Susanna, Breda Carlo, Sathyasaikumar Korrapati V, Muchowski Paul J, Schwarcz Robert, Kyriacou Charalambos P, Giorgini Flaviano
Department of Genetics, University of Leicester, Leicestershire, UK.
Fly (Austin). 2012 Apr-Jun;6(2):117-20. doi: 10.4161/fly.19999. Epub 2012 Apr 1.
Huntington disease (HD) is a fatal inherited neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein (htt). A pathological hallmark of the disease is the loss of a specific population of striatal neurons, and considerable attention has been paid to the role of the kynurenine pathway (KP) of tryptophan (TRP) degradation in this process. The KP contains three neuroactive metabolites: 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and kynurenic acid (KYNA). 3-HK and QUIN are neurotoxic, and are increased in the brains of early stage HD patients, as well as in yeast and mouse models of HD. Conversely, KYNA is neuroprotective and has been shown to be decreased in HD patient brains. We recently used a Drosophila model of HD to measure the neuroprotective effect of genetic and pharmacological inhibition of kynurenine monoxygenase (KMO)-the enzyme catalyzing the formation of 3-HK at a pivotal branch point in the KP. We found that KMO inhibition in Drosophila robustly attenuated neurodegeneration, and that this neuroprotection was correlated with reduced levels of 3-HK relative to KYNA. Importantly, we showed that KP metabolites are causative in this process, as 3-HK and KYNA feeding experiments modulated neurodegeneration. We also found that genetic inhibition of the upstream KP enzyme tryptophan-2,3-dioxygenase (TDO) was neuroprotective in flies. Here, we extend these results by reporting that genetic impairment of KMO or TDO is protective against the eclosion defect in HD model fruit flies. Our results provide further support for the possibility of therapeutic KP interventions in HD.
亨廷顿舞蹈症（HD）是一种致命的遗传性神经退行性疾病，由亨廷顿蛋白（htt）中的多聚谷氨酰胺扩增引起。该疾病的一个病理标志是特定纹状体神经元群体的丧失，并且色氨酸（TRP）降解的犬尿氨酸途径（KP）在这一过程中的作用受到了相当多的关注。KP包含三种具有神经活性的代谢产物：3-羟基犬尿氨酸（3-HK）、喹啉酸（QUIN）和犬尿喹啉酸（KYNA）。3-HK和QUIN具有神经毒性，在HD早期患者的大脑以及HD的酵母和小鼠模型中含量增加。相反，KYNA具有神经保护作用，并且已证实在HD患者大脑中含量降低。我们最近使用HD果蝇模型来测量犬尿氨酸单加氧酶（KMO）的基因和药物抑制的神经保护作用，KMO是在KP的一个关键分支点催化3-HK形成的酶。我们发现果蝇中的KMO抑制显著减轻了神经退行性变，并且这种神经保护作用与相对于KYNA的3-HK水平降低相关。重要的是，我们表明KP代谢产物在这一过程中具有因果关系，因为3-HK和KYNA喂养实验调节了神经退行性变。我们还发现上游KP酶色氨酸-2,3-双加氧酶（TDO）的基因抑制在果蝇中具有神经保护作用。在此，我们通过报告KMO或TDO的基因损伤对HD模型果蝇的羽化缺陷具有保护作用来扩展这些结果。我们的结果为在HD中进行治疗性KP干预的可能性提供了进一步的支持。
