Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradationvan der Goot, A. T., Zhu, W., Vazquez-Manrique, R. P., Seinstra, R. I., Dettmer, K., Michels, H., Farina, F., Krijnen, J., Melki, R., Buijsman, R. C., Silva, M. R., Thijssen, K. L., Kema, I. P., Neri, C., Oefner, P. J. & Nollen, E. A. A., 11-Sep-2012, In : Proceedings of the National Academy of Sciences of the United States of America. 109, 37, p. 14912-14917 6 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 11-Sep-2012|
- Huntington, longevity, HEAT-SHOCK-FACTOR, CAENORHABDITIS-ELEGANS, ALPHA-SYNUCLEIN, C-ELEGANS, IN-VIVO, KYNURENINE 3-MONOOXYGENASE, PARKINSONS-DISEASE, LEWY BODIES, LIFE-SPAN, PROTEOTOXICITY