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
  • Muscular Dystrophy, Duchenne/drug therapy*
  • Muscular Dystrophy, Duchenne/genetics
  • Muscular Dystrophy, Duchenne/pathology
  • Fluoxetine/pharmacology
  • Fluoxetine/therapeutic use*
  • Homeostasis/drug effects
  • Gene Knockdown Techniques
  • Drug Evaluation, Preclinical
  • Birefringence
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Animals
  • Evans Blue/metabolism
  • Survival Analysis
  • Serotonin Plasma Membrane Transport Proteins/metabolism
  • Molecular Sequence Data
  • Muscular Dystrophy, Animal/drug therapy*
  • Muscular Dystrophy, Animal/genetics
  • Muscular Dystrophy, Animal/pathology
  • Calcium/metabolism
  • Phenotype
  • Disease Models, Animal
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/physiology*
  • Morpholinos/pharmacology
  • Base Sequence
  • Stress, Mechanical
  • Gene Expression Profiling
  • Dystrophin/metabolism
  • Oligonucleotide Array Sequence Analysis
(all 31)
PubMed
24760771 Full text @ Hum. Mol. Genet.
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
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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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.