PUBLICATION
Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy
- Authors
- Waugh, T.A., Horstick, E., Hur, J., Jackson, S.W., Davidson, A.E., Li, X., Dowling, J.J.
- ID
- ZDB-PUB-140513-91
- Date
- 2014
- Source
- Human molecular genetics 23(17): 4651-62 (Journal)
- Registered Authors
- Dowling, Jim, Waugh, Trent
- Keywords
- none
- MeSH Terms
-
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/physiology*
- Gene Knockdown Techniques
- Drug Evaluation, Preclinical
- Homeostasis/drug effects
- Oligonucleotide Array Sequence Analysis
- Calcium/metabolism
- Muscular Dystrophy, Animal/drug therapy*
- Muscular Dystrophy, Animal/genetics
- Muscular Dystrophy, Animal/pathology
- Survival Analysis
- Base Sequence
- Phenotype
- Stress, Mechanical
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Muscular Dystrophy, Duchenne/drug therapy*
- Muscular Dystrophy, Duchenne/genetics
- Muscular Dystrophy, Duchenne/pathology
- Birefringence
- Evans Blue/metabolism
- Molecular Sequence Data
- Gene Expression Profiling
- Fluoxetine/pharmacology
- Fluoxetine/therapeutic use*
- Dystrophin/metabolism
- Animals
- Disease Models, Animal
- Morpholinos/pharmacology
- Serotonin Plasma Membrane Transport Proteins/metabolism
- PubMed
- 24760771 Full text @ Hum. Mol. Genet.
Citation
Waugh, T.A., Horstick, E., Hur, J., Jackson, S.W., Davidson, A.E., Li, X., Dowling, J.J. (2014) Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy. Human molecular genetics. 23(17):4651-62.
Abstract
Duchenne muscular dystrophy (DMD) is a common and relentlessly progressive muscle disease. Some interventions have been identified that modestly slow progression and prolong survival, but more meaningful therapies are lacking. The goal of this study is to identify new therapeutic pathways for DMD using a zebrafish model of the disease. To accomplish this, we performed a non-biased drug screen in sapje, a zebrafish line with a recessive nonsense mutation in dystrophin. We identified 6 positive hits (out of 640 total drugs tested) by their ability to prevent abnormal birefringence in sapje. Follow up analyses demonstrated that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), provided the most substantial benefit. Morpholino-based experimentation confirmed that modulation of the serotonin pathway alone can prevent the dystrophic phenotype, and transcriptomic analysis revealed changes in calcium homeostasis as a potential mechanism. In all, we demonstrate that monoamine agonists can prevent disease in a vertebrate model of DMD. Given the safe and widespread use of SSRIs in clinical practice, our study identifies an attractive target pathway for therapy development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping