van der Goot, Annemieke T. and Zhu, Wentao and Vazquez-Manrique, Rafael P. and Seinstra, Renee I. and Dettmer, Katja and Michels, Helen and Farina, Francesca and Krijnen, Jasper and Melki, Ronald and Buijsman, Rogier C. and Silva, Mariana Ruiz and Thijssen, Karen L. and Kema, Ido P. and Neri, Christian and Oefner, Peter J. and Nollen, Ellen A. A. (2012) Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109 (37). pp. 14912-14917. ISSN 0027-8424,
Full text not available from this repository. (Request a copy)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 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEAT-SHOCK-FACTOR; CAENORHABDITIS-ELEGANS; ALPHA-SYNUCLEIN; KYNURENINE 3-MONOOXYGENASE; IN-VITRO; DISEASE; PROTEOSTASIS; EXPRESSION; IDENTIFICATION; LONGEVITY; Huntington; longevity |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 May 2020 05:59 |
| Last Modified: | 06 May 2020 05:59 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18116 |
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