PNAS:帕金森、痴呆症等神经衰退疾病如何逆转?与氨基酸代谢有关
2016/05/05
保护神经细胞是对抗神经变性疾病的一个关键治疗主题。但是,如何减缓、甚至于阻止神经细胞的衰退?这一直是科研人员努力破解的难题。近期,来自于英国莱斯特大学的遗传学家Flaviano Giorgini团队从氨基酸代谢入手,成功通过控制有害代谢中间产物物的合成而减缓果蝇神经细胞的损伤。


目前,对于老年痴呆症(AD)、帕金森(PD)、亨廷顿氏舞蹈症(HD)等神经类衰退疾病依然没有根治的医疗药物和技术出现。现有的药物仅仅针对患者症状进行治疗,并不能减缓或者逆转病情发展。其中,帕金森症起病隐袭,进展缓慢。等到症状突显患者确诊之时,往往70%的神经细胞已经受损。所以,作为多发于中老年群体、且有年轻化趋势的一类神经变性疾病,阿尔兹海默症、帕金森症等一直是科研机构、医药企业意欲攀登却艰难重重的高峰。

保护神经细胞是对抗神经变性疾病的一个关键治疗主题。但是,如何减缓、甚至于阻止神经细胞的衰退?这一直是科研人员努力破解的难题。

近期,来自于英国莱斯特大学的遗传学家Flaviano Giorgini团队从氨基酸代谢入手,成功通过控制有害代谢中间产物的合成而减缓果蝇神经细胞的受损。相关研究成果于4月25日发表在PNAS期刊。

控制患病果蝇有毒代谢产物的合成,有效保护神经细胞免于受损

Giorgini团队以黑腹果蝇(Drosophila melanogaster)作为研究模型,以此解析犬尿氨酸代谢通路(kynurenine pathway)中的中间产物如何引发包括阿尔兹海默症、亨廷顿舞蹈症、帕金森症等在内疾病相关神经细胞的衰亡。

之前的研究已经证实,神经类疾病患者会过表达一些代谢物,从而损伤神经细胞。所以,Giorgini团队从基因、化学药物两条途径入手试验,都证实可以有效降低神经系统中有毒产物的合成。

研究人员通过抑制抑制犬尿氨酸通路中的两个关键酶(TDO、KMO)活性,能够降低有毒代谢产物的合成、增加犬尿氨酸的产生,从而有效改善患病果蝇(亨廷顿病、阿尔兹海默症、帕金森)的症状。

犬尿氨酸是这一代谢通路中的关键物质,通过平衡其他有害代谢产物的合成,从而保护神经细胞。Giorgini教授解释,犬尿氨酸通路中的“好”“坏”代谢产物的平衡是维持健康的核心。一旦失去平衡且坏物质占上风,则会滋生祸害、导致疾病。而抑制TDO、KMO两类酶的活力,能够将平衡拉回“好”的层面上。

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  • Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

    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.

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