論文 - 詳細
| RRC ID | 46448 |
|---|---|
| 著者 | Staab TA, Griffen TC, Corcoran C, Evgrafov O, Knowles JA, Sieburth D. |
| タイトル | The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. |
| ジャーナル | PLoS Genet |
| Abstract |
The Nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration, aging, and cancer. Here, we report a novel role for the Caenorhabditis elegans Nrf homolog SKN-1 in regulating synaptic transmission at neuromuscular junctions (NMJs). Activation of SKN-1, either by acute pharmacological treatment with the mitochondrial toxin sodium arsenite or by mutations that cause constitutive SKN-1 activation, results in defects in neuromuscular function. Additionally, elimination of the conserved WD40 repeat protein WDR-23, a principal negative regulator of SKN-1, results in impaired locomotion and synaptic vesicle and neuropeptide release from cholinergic motor axons. Mutations that abolish skn-1 activity restore normal neuromuscular function to wdr-23 mutants and animals treated with toxin. We show that negative regulation of SKN-1 by WDR-23 in the intestine, but not at neuromuscular junctions, is necessary and sufficient for proper neuromuscular function. WDR-23 isoforms differentially localize to the outer membranes of mitochondria and to nuclei, and the effects of WDR-23 on neuromuscular function are dependent on its interaction with cullin E3 ubiquitin ligase. Finally, whole-transcriptome RNA sequencing of wdr-23 mutants reveals an increase in the expression of known SKN-1/Nrf2-regulated stress-response genes, as well as neurotransmission genes not previously implicated in SKN-1/Nrf2 responses. Together, our results indicate that SKN-1/Nrf2 activation may be a mechanism through which cellular stress, detected in one tissue, affects cellular function of a distal tissue through endocrine signaling. These results provide insight into how SKN-1/Nrf2 might protect the nervous system from damage in response to oxidative stress. |
| 巻・号 | 9(3) |
| ページ | e1003354 |
| 公開日 | 2013-3-1 |
| DOI | 10.1371/journal.pgen.1003354 |
| PII | PGENETICS-D-12-02463 |
| PMID | 23555279 |
| PMC | PMC3605294 |
| MeSH | Animals Arsenites / pharmacology Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans* / physiology Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Cell Nucleus / genetics Cell Nucleus / metabolism Cullin Proteins DNA-Binding Proteins* / genetics DNA-Binding Proteins* / metabolism Mitochondrial Membranes / drug effects Mutation Nervous System* / drug effects Nervous System* / metabolism Neuromuscular Junction / genetics Neuromuscular Junction / physiology Oxidative Stress / drug effects* Sodium Compounds / pharmacology Synaptic Transmission / genetics Synaptic Transmission / physiology Transcription Factors* / genetics Transcription Factors* / metabolism |
| IF | 5.175 |
| 引用数 | 38 |
| WOS 分野 | GENETICS & HEREDITY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 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 | tm1817 tm1108 |