論文 - 詳細
| RRC ID | 53449 |
|---|---|
| 著者 | Julien C, Lissouba A, Madabattula S, Fardghassemi Y, Rosenfelt C, Androschuk A, Strautman J, Wong C, Bysice A, O'sullivan J, Rouleau GA, Drapeau P, Parker JA, Bolduc FV. |
| タイトル | Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms. |
| ジャーナル | Hum Mol Genet |
| Abstract |
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N-acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP. |
| 巻・号 | 25(6) |
| ページ | 1088-99 |
| 公開日 | 2016-3-15 |
| DOI | 10.1093/hmg/ddv632 |
| PII | ddv632 |
| PMID | 26744324 |
| PMC | PMC4764191 |
| MeSH | Adenosine Triphosphatases / genetics Animals Caenorhabditis elegans Disease Models, Animal* Drosophila Endoplasmic Reticulum / drug effects Endoplasmic Reticulum Stress / drug effects Endoplasmic Reticulum Stress / genetics Female Humans Locomotion / drug effects Locomotion / genetics Microtubules / drug effects Microtubules / metabolism Mutation Phenazines / pharmacology Phenotype Spastic Paraplegia, Hereditary / drug therapy* Spastic Paraplegia, Hereditary / genetics Zebrafish |
| IF | 5.101 |
| 引用数 | 12 |
| 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 | 5 |
| 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 | tm3056 tm683 |