RRC ID 46460
Author van der Goot AT, Zhu W, Vázquez-Manrique RP, Seinstra RI, Dettmer K, Michels H, Farina F, Krijnen J, Melki R, Buijsman RC, Ruiz Silva M, Thijssen KL, Kema IP, Neri C, Oefner PJ, Nollen EA.
Title Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation.
Journal Proc Natl Acad Sci U S A
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.
Volume 109(37)
Pages 14912-7
Published 2012-9-11
DOI 10.1073/pnas.1203083109
PII 1203083109
PMID 22927396
PMC PMC3443121
MeSH Aging / metabolism Aging / physiology* Amyloid beta-Peptides / metabolism Animals Animals, Genetically Modified Caenorhabditis elegans Chromatography, Liquid Computational Biology DNA Primers / genetics Fertility / genetics Homeostasis / physiology* Immunoblotting Longevity / genetics Peptides / metabolism RNA Interference Reverse Transcriptase Polymerase Chain Reaction Tandem Mass Spectrometry Tryptophan / chemistry Tryptophan / metabolism* Tryptophan Oxygenase / antagonists & inhibitors Tryptophan Oxygenase / metabolism* alpha-Synuclein / toxicity*
IF 9.412
Times Cited 91
C.elegans tm4547 tm4529 tm4627 tm4924