; Seinstra, Renée I. ; Dettmer, Katja
; Michels, Helen ; Farina, Francesca ; Krijnen, Jasper ; Melki, Ronald ; Buijsman, Rogier C. ; Ruiz Silva, Mariana ; Thijssen, Karen L. ; Kema, Ido P. ; Neri, Christian
; Oefner, Peter J.
; Nollen, Ellen A. A. | Item type: | Article | ||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America | ||||||||||||||||||||||||||||||||||||||||
| Publisher: | NATL ACAD SCIENCES | ||||||||||||||||||||||||||||||||||||||||
| Place of Publication: | WASHINGTON | ||||||||||||||||||||||||||||||||||||||||
| Volume: | 109 | ||||||||||||||||||||||||||||||||||||||||
| Number of Issue or Book Chapter: | 37 | ||||||||||||||||||||||||||||||||||||||||
| Page Range: | pp. 14912-7 | ||||||||||||||||||||||||||||||||||||||||
| Date: | 2012 | ||||||||||||||||||||||||||||||||||||||||
| Institutions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) | ||||||||||||||||||||||||||||||||||||||||
| Identification Number: |
| ||||||||||||||||||||||||||||||||||||||||
| Related URLs: |
| ||||||||||||||||||||||||||||||||||||||||
| Classification: |
| ||||||||||||||||||||||||||||||||||||||||
| Keywords: | HEAT-SHOCK-FACTOR; CAENORHABDITIS-ELEGANS; ALPHA-SYNUCLEIN; KYNURENINE 3-MONOOXYGENASE; IN-VITRO; DISEASE; PROTEOSTASIS; EXPRESSION; IDENTIFICATION; LONGEVITY; Huntington; longevity | ||||||||||||||||||||||||||||||||||||||||
| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine | ||||||||||||||||||||||||||||||||||||||||
| Status: | Published | ||||||||||||||||||||||||||||||||||||||||
| Refereed: | Yes, this version has been refereed | ||||||||||||||||||||||||||||||||||||||||
| Created at the University of Regensburg: | Partially | ||||||||||||||||||||||||||||||||||||||||
| Item ID: | 30571 |
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 ...

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.
Metadata last modified: 14 Oct 2025 05:49
Altmetric