論文 - 詳細
| RRC ID | 46460 |
|---|---|
| 著者 | 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. |
| タイトル | Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. |
| ジャーナル | 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. |
| 巻・号 | 109(37) |
| ページ | 14912-7 |
| 公開日 | 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 |
| 引用数 | 91 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 14 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm4547 tm4529 tm4627 tm4924 |