Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites
Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites
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DOI：
10.1073/pnas.1604453113
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发表时间：
2016-05-10
影响因子：
11.1
通讯作者：
Giorgini, Flaviano
中科院分区：
文献类型：
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作者：
Breda, Carlo;Sathyasaikumar, Korrapati V.;Giorgini, Flaviano
色氨酸（TRP）降解的犬尿氨酸途径（KP）的代谢物与多种神经退行性疾病的发病机制密切相关。最近的工作强调了抑制该途径中的两种关键调节酶-犬尿氨酸-3-单加氧酶（KMO）和色氨酸-2，3-双加氧酶（TDO）的治疗潜力。许多证据表明，KMO抑制的功效来自于使神经毒性[3-羟基犬尿氨酸（3-HK）;喹啉酸（QUIN）]和神经保护性[犬尿氨酸（KYNA）] KP代谢物之间的不平衡正常化。然而，尚不清楚TDO抑制是否通过类似的机制具有保护性，或者这是否是由于TDO底物TRP水平的增加。在此，我们发现KYNA相对于3-HK的水平增加可能是亨廷顿病的果蝇模型中TDO抑制所赋予的保护的核心，并且TRP治疗通过将KP通量转向KYNA合成而强烈地减少神经变性。在阿尔茨海默氏症和帕金森氏症的果蝇模型中，我们提供了遗传学证据，表明抑制TDO或KMO可以改善运动性能，改善缩短的寿命，以及减少阿尔茨海默氏症模型果蝇的神经变性。重要的是，我们发现用化学TDO抑制剂治疗在这些模型中具有强大的保护作用。因此，我们的工作强烈支持靶向KP作为几种主要神经退行性疾病的潜在治疗策略，并表明神经活性KP代谢物水平的改变可能是几种治疗益处的基础。
Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.