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
  • Homeostasis/drug effects
  • Morpholinos/pharmacology
  • Base Sequence
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Serotonin Plasma Membrane Transport Proteins/metabolism
  • Molecular Sequence Data
  • Stress, Mechanical
  • Survival Analysis
  • Dystrophin/metabolism
  • Disease Models, Animal
  • Evans Blue/metabolism
  • Muscular Dystrophy, Duchenne/drug therapy*
  • Muscular Dystrophy, Duchenne/genetics
  • Muscular Dystrophy, Duchenne/pathology
  • Animals
  • Calcium/metabolism
  • Phenotype
  • Oligonucleotide Array Sequence Analysis
  • Muscular Dystrophy, Animal/drug therapy*
  • Muscular Dystrophy, Animal/genetics
  • Muscular Dystrophy, Animal/pathology
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/physiology*
  • Birefringence
  • Gene Expression Profiling
  • Drug Evaluation, Preclinical
  • Fluoxetine/pharmacology
  • Fluoxetine/therapeutic use*
  • Gene Knockdown Techniques
(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
Figures
No images available
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ta222a
    Point Mutation
    1 - 1 of 1
    Show
    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    slc6a4aMO1-slc6a4aMRPHLNO
    slc6a4bMO1-slc6a4bMRPHLNO
    1 - 2 of 2
    Show
    Fish
    Antibodies
    Orthology
    Engineered Foreign Genes
    No data available
    Mapping