Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells

Abstract Dysferlinopathy is a progressive muscle disorder that includes limb‐girdle muscular dystrophy type 2B and Miyoshi myopathy (MM). It is caused by mutations in the dysferlin (DYSF) gene, whose function is to reseal the muscular membrane. Treatment with proteasome inhibitor MG‐132 has been sho...

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Autores principales:	Yuko Kokubu, Tomoko Nagino, Katsunori Sasa, Tatsuo Oikawa, Katsuya Miyake, Akiko Kume, Mikiko Fukuda, Hiromitsu Fuse, Ryuichi Tozawa, Hidetoshi Sakurai
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2019
Materias:	Induced pluripotent stem cells Skeletal muscle Drug target Muscular dystrophy Differentiation Myosin heavy chain Medicine (General) R5-920 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/b07e2c3175334def8fbba6cc177a30d7
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spelling	oai:doaj.org-article:b07e2c3175334def8fbba6cc177a30d72021-11-30T19:15:37ZPhenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells2157-65802157-656410.1002/sctm.18-0280https://doaj.org/article/b07e2c3175334def8fbba6cc177a30d72019-10-01T00:00:00Zhttps://doi.org/10.1002/sctm.18-0280https://doaj.org/toc/2157-6564https://doaj.org/toc/2157-6580Abstract Dysferlinopathy is a progressive muscle disorder that includes limb‐girdle muscular dystrophy type 2B and Miyoshi myopathy (MM). It is caused by mutations in the dysferlin (DYSF) gene, whose function is to reseal the muscular membrane. Treatment with proteasome inhibitor MG‐132 has been shown to increase misfolded dysferlin in fibroblasts, allowing them to recover their membrane resealing function. Here, we developed a screening system based on myocytes from MM patient‐derived induced pluripotent stem cells. According to the screening, nocodazole was found to effectively increase the level of dysferlin in cells, which, in turn, enhanced membrane resealing following injury by laser irradiation. Moreover, the increase was due to microtubule disorganization and involved autophagy rather than the proteasome degradation pathway. These findings suggest that increasing the amount of misfolded dysferlin using small molecules could represent an effective future clinical treatment for dysferlinopathy. Stem Cells Translational Medicine 2019;8:1017–1029Yuko KokubuTomoko NaginoKatsunori SasaTatsuo OikawaKatsuya MiyakeAkiko KumeMikiko FukudaHiromitsu FuseRyuichi TozawaHidetoshi SakuraiWileyarticleInduced pluripotent stem cellsSkeletal muscleDrug targetMuscular dystrophyDifferentiationMyosin heavy chainMedicine (General)R5-920CytologyQH573-671ENStem Cells Translational Medicine, Vol 8, Iss 10, Pp 1017-1029 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Induced pluripotent stem cells Skeletal muscle Drug target Muscular dystrophy Differentiation Myosin heavy chain Medicine (General) R5-920 Cytology QH573-671
spellingShingle	Induced pluripotent stem cells Skeletal muscle Drug target Muscular dystrophy Differentiation Myosin heavy chain Medicine (General) R5-920 Cytology QH573-671 Yuko Kokubu Tomoko Nagino Katsunori Sasa Tatsuo Oikawa Katsuya Miyake Akiko Kume Mikiko Fukuda Hiromitsu Fuse Ryuichi Tozawa Hidetoshi Sakurai Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells
description	Abstract Dysferlinopathy is a progressive muscle disorder that includes limb‐girdle muscular dystrophy type 2B and Miyoshi myopathy (MM). It is caused by mutations in the dysferlin (DYSF) gene, whose function is to reseal the muscular membrane. Treatment with proteasome inhibitor MG‐132 has been shown to increase misfolded dysferlin in fibroblasts, allowing them to recover their membrane resealing function. Here, we developed a screening system based on myocytes from MM patient‐derived induced pluripotent stem cells. According to the screening, nocodazole was found to effectively increase the level of dysferlin in cells, which, in turn, enhanced membrane resealing following injury by laser irradiation. Moreover, the increase was due to microtubule disorganization and involved autophagy rather than the proteasome degradation pathway. These findings suggest that increasing the amount of misfolded dysferlin using small molecules could represent an effective future clinical treatment for dysferlinopathy. Stem Cells Translational Medicine 2019;8:1017–1029
format	article
author	Yuko Kokubu Tomoko Nagino Katsunori Sasa Tatsuo Oikawa Katsuya Miyake Akiko Kume Mikiko Fukuda Hiromitsu Fuse Ryuichi Tozawa Hidetoshi Sakurai
author_facet	Yuko Kokubu Tomoko Nagino Katsunori Sasa Tatsuo Oikawa Katsuya Miyake Akiko Kume Mikiko Fukuda Hiromitsu Fuse Ryuichi Tozawa Hidetoshi Sakurai
author_sort	Yuko Kokubu
title	Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells
title_short	Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells
title_full	Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells
title_fullStr	Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells
title_full_unstemmed	Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells
title_sort	phenotypic drug screening for dysferlinopathy using patient‐derived induced pluripotent stem cells
publisher	Wiley
publishDate	2019
url	https://doaj.org/article/b07e2c3175334def8fbba6cc177a30d7
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Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells

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