Haploinsufficiency of mechanistic target of rapamycin ameliorates bag3 cardiomyopathy in adult zebrafish
| Autor: | Xiaolei Xu, Wang Lei, René R. Sevag Packard, Yong Wang, Alexey V. Dvornikov, Tzung K. Hsiai, Matthew R. Lowerison, Yonghe Ding, Yuji Zhang, Xiao Ma, Zhang Hong, Jun Chen, Xueying Lin |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mutant Neuroscience (miscellaneous) lcsh:Medicine Medicine (miscellaneous) Haploinsufficiency Biology BAG3 General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Immunology and Microbiology (miscellaneous) Transcription Activator-Like Effector Nucleases mtor lcsh:Pathology Animals Amino Acid Sequence Zebrafish Mechanistic target of rapamycin PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Transcription activator-like effector nuclease Base Sequence Gene Expression Profiling Myocardium TOR Serine-Threonine Kinases lcsh:R Zebrafish Proteins Zebra biology.organism_classification Cell biology dilated cardiomyopathy Phenotype 030104 developmental biology Proteostasis danio rerio Mutation bcl2-associated athanogene 3 biology.protein Apoptosis Regulatory Proteins Cardiomyopathies 030217 neurology & neurosurgery Research Article Signal Transduction lcsh:RB1-214 |
| Zdroj: | Disease Models & Mechanisms, Vol 12, Iss 10 (2019) Disease Models & Mechanisms |
| ISSN: | 1754-8411 1754-8403 |
| Popis: | The adult zebrafish is an emerging vertebrate model for studying human cardiomyopathies; however, whether the simple zebrafish heart can model different subtypes of cardiomyopathies, such as dilated cardiomyopathy (DCM), remains elusive. Here, we generated and characterized an inherited DCM model in adult zebrafish and used this model to search for therapeutic strategies. We employed transcription activator-like effector nuclease (TALEN) genome editing technology to generate frame-shift mutants for the zebrafish ortholog of human BCL2-associated athanogene 3 (BAG3), an established DCM-causative gene. As in mammals, the zebrafish bag3 homozygous mutant (bag3e2/e2) exhibited aberrant proteostasis, as indicated by impaired autophagy flux and elevated ubiquitinated protein aggregation. Through comprehensive phenotyping analysis of the mutant, we identified phenotypic traits that resembled DCM phenotypes in mammals, including cardiac chamber enlargement, reduced ejection fraction characterized by increased end-systolic volume/body weight (ESV/BW), and reduced contractile myofibril activation kinetics. Nonbiased transcriptome analysis identified the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling in bag3e2/e2 mutant hearts. Further genetic studies showed that mtorxu015/+, an mTOR haploinsufficiency mutant, repaired abnormal proteostasis, improved cardiac function and rescued the survival of the bag3e2/e2 mutant. This study established the bag3e2/e2 mutant as a DCM model in adult zebrafish and suggested mtor as a candidate therapeutic target gene for BAG3 cardiomyopathy. Summary: This study shows that adult bag3 knockout mutant zebrafish can be used as a model for DCM, and haploinsufficiency of mTOR is cardioprotective. |
| Databáze: | OpenAIRE |
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