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
リソース情報
線虫 tm3056 tm683