Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation
Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation
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DOI：
10.1073/pnas.1203083109
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发表时间：
2012-09-11
影响因子：
11.1
通讯作者：
Nollen, Ellen A. A.
中科院分区：
文献类型：
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作者：
van der Goot, Annemieke T.;Zhu, Wentao;Nollen, Ellen A. A.
聚集倾向蛋白的毒性被认为在衰老以及帕金森和阿尔茨海默病等与年龄相关的神经疾病中发挥着重要作用。在这里，我们确定色氨酸2，3-双加氧酶(TDO-2)是色氨酸降解的犬尿氨酸途径中的第一个酶，在秀丽线虫模型中是与年龄相关的α-突触核蛋白毒性的代谢调节因子。Tdo-2的缺失也抑制了其他异源聚集倾向蛋白的毒性，包括淀粉样β蛋白和聚谷氨酰胺蛋白，以及内源性亚稳蛋白，这些蛋白是正常蛋白质动态平衡的传感器。这一发现表明Tdo-2作为蛋白质稳态的一般调节因子发挥作用。对作用于tdo-2下游的酶突变的线虫菌株代谢物水平的分析表明，这种毒性抑制独立于犬尿氨酸途径的下游代谢物。耗尽TDO-2会增加色氨酸水平，而给蠕虫喂食额外的L-色氨酸也能抑制毒性，这表明TDO-2通过色氨酸调节蛋白毒性。Tdo-2的耗尽延长了这些蠕虫的寿命。综上所述，这些结果暗示TDO-2是年龄相关蛋白质稳态和寿命的代谢开关。将TDO和吲哚胺2，3-双加氧酶作为进化上保守的TDO-2的人类同源基因，干预色氨酸代谢可能为减少衰老和老年相关疾病的蛋白毒性提供途径。
Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer's diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related alpha-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-beta and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that tdo-2 functions as a general regulator of protein homeostasis. Analysis of metabolite levels in C. elegans strains with mutations in enzymes that act downstream of tdo-2 indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of tdo-2 increases tryptophan levels, and feeding worms with extra L-tryptophan also suppresses toxicity, suggesting that tdo-2 regulates proteotoxicity through tryptophan. Depletion of tdo-2 extends lifespan in these worms. Together, these results implicate tdo-2 as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.