PUBLICATION
Zebrafish model of amyloid light chain cardiotoxicity: regeneration vs degeneration
- Authors
- Mishra, S., Joshi, S., Ward, J.E., Buys, E.P., Mishra, D., Mishra, D., Morgado, I., Fisch, S., Lavatelli, F., Merlini, G., Dorbala, S., MacRae, C.A., Liao, R.
- ID
- ZDB-PUB-190316-12
- Date
- 2019
- Source
- American journal of physiology. Heart and circulatory physiology 316(5): H1158-H1166 (Journal)
- Registered Authors
- Buys, Eva Plovie, MacRae, Calum A.
- Keywords
- amyloidosis, in vivo model cardiovascular disease, proteotoxicity, transgenic zebrafish
- MeSH Terms
-
- Amyloidosis/embryology
- Amyloidosis/genetics
- Amyloidosis/metabolism*
- Amyloidosis/physiopathology
- Animals
- Animals, Genetically Modified
- Apoptosis*
- Cardiomyopathies/embryology
- Cardiomyopathies/genetics
- Cardiomyopathies/metabolism*
- Cardiomyopathies/physiopathology
- Cardiotoxicity
- Cell Proliferation*
- Disease Models, Animal
- Humans
- Immunoglobulin lambda-Chains/genetics
- Immunoglobulin lambda-Chains/metabolism*
- Myocardium/metabolism*
- Myocardium/pathology
- Regeneration*
- Zebrafish
- PubMed
- 30875258 Full text @ Am. J. Physiol. Heart Circ. Physiol.
Citation
Mishra, S., Joshi, S., Ward, J.E., Buys, E.P., Mishra, D., Mishra, D., Morgado, I., Fisch, S., Lavatelli, F., Merlini, G., Dorbala, S., MacRae, C.A., Liao, R. (2019) Zebrafish model of amyloid light chain cardiotoxicity: regeneration vs degeneration. American journal of physiology. Heart and circulatory physiology. 316(5):H1158-H1166.
Abstract
Cardiac dysfunction is the most frequent cause of morbidity and mortality in immunoglobulin light chain (AL) amyloidosis. Previously published transgenic animal models of AL amyloidosis have not recapitulated the key phenotype of cardiac dysfunction seen in AL amyloidosis which has limited our understanding of the disease mechanisms in vivo, as well as the development of targeted AL therapeutics. We have developed a transgenic zebrafish model in which a AL patient-derived lambda light chain (LC) is conditionally expressed in the liver under the control of UAS-Gal4 enhancer system. Circulating LC levels of 125 µg/ml in these transgenic zebrafish are comparable to median pathologic serum LC levels. Functional analysis links abnormal contractile function with evidence of cellular and molecular proteotoxicity in the heart, including increased cell death and autophagy. However, despite pathologic and functional phenotypes analogous to human AL, the lifespan of the transgenic fish is comparable to control fish without the expressed AL-LC transgene. Nuclear labeling experiments suggest increased cardiac proliferation in the transgenic fish, which can be counteracted by treatment with a small molecule proliferation inhibitor leading to increased zebrafish mortality due to cardiac apoptosis and functional deterioration. This transgenic zebrafish model provides a platform to further study underlying AL disease mechanisms in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping