Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation

作者：van der Goot Annemieke T; Zhu Wentao; Vazquez Manrique Rafael P; Seinstra Renee I; Dettmer Katja; Michels Helen; Farina Francesca; Krijnen Jasper; Melki Ronald; Buijsman Rogier C; Silva Mariana Ruiz; Thijssen Karen L; Kema Ido P; Neri Christian; Oefner Peter J; Nollen Ellen A A^*

来源：Proceedings of the National Academy of Sciences, 2012, 109(37): 14912-14917.

DOI：10.1073/pnas.1203083109

• Huntington
• longevity

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.

• 出版日期2012-9-11