title: Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation.
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.
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Annemieke T
authors.initials: AT
authors.lastname: van der Goot
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhu
authors.forename: Rafael P
authors.initials: RP
authors.lastname: Vázquez-Manrique
authors.forename: Renée I
authors.initials: RI
authors.lastname: Seinstra
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.forename: Helen
authors.initials: H
authors.lastname: Michels
authors.forename: Francesca
authors.initials: F
authors.lastname: Farina
authors.forename: Jasper
authors.initials: J
authors.lastname: Krijnen
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
authors.forename: Rogier C
authors.initials: RC
authors.lastname: Buijsman
authors.forename: Mariana
authors.initials: M
authors.lastname: Ruiz Silva
authors.forename: Karen L
authors.initials: KL
authors.lastname: Thijssen
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.forename: Christian
authors.initials: C
authors.lastname: Neri
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.forename: Ellen A A
authors.initials: EA
authors.lastname: Nollen
mesh_terms: D000375:Aging / Q000378:metabolism / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D002853:Chromatography, Liquid; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D005298:Fertility / Q000235:genetics; D006706:Homeostasis / Q000502:physiology*; D015151:Immunoblotting; D008136:Longevity / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051844:alpha-Synuclein / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D017931:DNA Primers; D010455:Peptides; D051844:alpha-Synuclein; C097188:polyglutamine; D014364:Tryptophan; D014366:Tryptophan Oxygenase