Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy.
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.
Department of Pediatrics.
Trent A
TA
Waugh
Department of Pediatrics.
Eric
E
Horstick
Department of Neurology, and.
Junguk
J
Hur
Department of Pediatrics.
Samuel W
SW
Jackson
Division of Neurology and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada.
Ann E
AE
Davidson
Department of Pediatrics.
Xingli
X
Li
Department of Pediatrics, Department of Neurology, and Department of Neuroscience, University of Michigan, Ann Arbor, MI 48109-2200, USA Division of Neurology and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada Department of Paediatrics, and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada james.dowling@sickkids.ca.
James J
JJ
Dowling
D000818:Animals; D001483:Base Sequence; D001718:Birefringence; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016189:Dystrophin / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D005070:Evans Blue / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006706:Homeostasis / Q000187:drug effects; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000494:pharmacology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D016019:Survival Analysis; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000502:physiology*
D016189:Dystrophin; D060172:Morpholinos; D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; D005070:Evans Blue; D002118:Calcium