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Pathogenic mechanisms
B17 Delaying ageing and the ageing-associated decline in protein homeostasis by inhibition of tryptophan degradation
  1. AT van der Goot1,
  2. W Zhu2,
  3. RI Seinstra1,
  4. J Krijnen3,
  5. M Ruiz Silva1,
  6. KL Thijssen1,
  7. PJ Oefner2,
  8. IP Kema3,
  9. EAA Nollen1
  1. 1European Institute for the Biology of Aging, University Medical Center Groningen, Groningen, The Netherlands
  2. 2Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
  3. 3Department of Laboratory Medicine, University of Groningen, University Medical Centre Groningen, The Netherlands

Abstract

Toxicity of aggregation-prone proteins is thought to play an important role in ageing and age-related neurological diseases like Parkinson's and Alzheimer's disease. 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 C. elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and of endogenous meta-stable proteins that are sensors of normal protein homeostasis. This 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 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 ageing and age-related diseases.

  • Tryptophan
  • TDO-2
  • c. elegans
  • ageing
  • aggregation-prone proteins
  • protein toxicity

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