Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation |
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Authors: | Annemieke T van der Goot Wentao Zhu Rafael P Vázquez-Manrique Renée I Seinstra Katja Dettmer Helen Michels Francesca Farina Jasper Krijnen Ronald Melki Rogier C Buijsman Mariana Ruiz Silva Karen L Thijssen Ido P Kema Christian Neri Peter J Oefner Ellen A A Nollen |
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Affiliation: | Departments of Genetics and Laboratory Medicine, University of Groningen, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands. |
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Abstract: | 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 α-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β 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. |
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Keywords: | Huntington longevity |
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