Characterization of a zebrafish model of congenital myopathy for therapeutic developments
Embargo Date
2027-02-28
OA Version
Citation
Abstract
Zebrafish are a well-established model to study skeletal muscle diseases and have emerged as a preclinical model for therapeutic developments. KLHL41 is a protein-coding gene that is involved in the development and differentiation of skeletal muscle. Mutations in KLHL41 result in a severe form of nemaline myopathy for which no treatments are currently available. Therefore, to perform small molecule in vivo phenotypic screening for therapeutic development in nemaline myopathy, a zebrafish model of KLHL41 deficiency is developed. This thesis focuses on identifying structural and functional deficits in KLHL41 deficiency in zebrafish to develop a small molecule screening strategy to identify effective small molecules. The structural changes in klhl41b mutants cause a physiologically detrimental phenotype that can be used for drug discovery through the analysis of swimming behavior. Mutant zebrafish exhibit disorganized sarcomeres, smaller myofibrils, and nemaline bodies that lead to a reduced swimming behavior. Finally, a quantitative swimming behavior assay was developed and optimized for conducting small molecule screening in the klhl41b fish model. In future studies, this model will be used to identify effective small molecules to treat KLHL41-nemaline myopathy and related
disorders.