; 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. | Dokumentenart: | Artikel | ||||||||||||||||||||||||||||||||||||||||
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| Titel eines Journals oder einer Zeitschrift: | Proceedings of the National Academy of Sciences of the United States of America | ||||||||||||||||||||||||||||||||||||||||
| Verlag: | NATL ACAD SCIENCES | ||||||||||||||||||||||||||||||||||||||||
| Ort der Veröffentlichung: | WASHINGTON | ||||||||||||||||||||||||||||||||||||||||
| Band: | 109 | ||||||||||||||||||||||||||||||||||||||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 37 | ||||||||||||||||||||||||||||||||||||||||
| Seitenbereich: | S. 14912-7 | ||||||||||||||||||||||||||||||||||||||||
| Datum: | 2012 | ||||||||||||||||||||||||||||||||||||||||
| Institutionen: | Medizin > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) | ||||||||||||||||||||||||||||||||||||||||
| Identifikationsnummer: |
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| Stichwörter / Keywords: | HEAT-SHOCK-FACTOR; CAENORHABDITIS-ELEGANS; ALPHA-SYNUCLEIN; KYNURENINE 3-MONOOXYGENASE; IN-VITRO; DISEASE; PROTEOSTASIS; EXPRESSION; IDENTIFICATION; LONGEVITY; Huntington; longevity | ||||||||||||||||||||||||||||||||||||||||
| Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||||||||||||||||||||||||||||||||||||||
| Status: | Veröffentlicht | ||||||||||||||||||||||||||||||||||||||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||||||||||||||||||||||||||||||||||||||
| An der Universität Regensburg entstanden: | Zum Teil | ||||||||||||||||||||||||||||||||||||||||
| Dokumenten-ID: | 30571 |
Zusammenfassung
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 ...

Zusammenfassung
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.
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