Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins

Mutations in the human LMNA gene cause a collection of diseases called laminopathies, which includes muscular dystrophy and dilated cardiomyopathy. The LMNA gene encodes lamins, filamentous proteins that form a meshwork on the inner side of the nuclear envelope. How mutant lamins cause muscle diseas...

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Autores principales:	Gary S. Coombs, Jose L. Rios-Monterrosa, Shuping Lai, Qiang Dai, Ashley C. Goll, Margaret R. Ketterer, Maria F. Valdes, Nnamdi Uche, Ivor J. Benjamin, Lori L. Wallrath
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Drosophila Lamins Muscular dystrophy Nuclear envelope Reductive stress Medicine (General) R5-920 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4c9bdf11cf72460381870a3509fc100a
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spelling	oai:doaj.org-article:4c9bdf11cf72460381870a3509fc100a2021-12-04T04:34:04ZModulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins2213-231710.1016/j.redox.2021.102196https://doaj.org/article/4c9bdf11cf72460381870a3509fc100a2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2213231721003566https://doaj.org/toc/2213-2317Mutations in the human LMNA gene cause a collection of diseases called laminopathies, which includes muscular dystrophy and dilated cardiomyopathy. The LMNA gene encodes lamins, filamentous proteins that form a meshwork on the inner side of the nuclear envelope. How mutant lamins cause muscle disease is not well understood, and treatment options are currently limited. To understand the pathological functions of mutant lamins so that therapies can be developed, we generated new Drosophila models and human iPS cell-derived cardiomyocytes. In the Drosophila models, muscle-specific expression of the mutant lamins caused nuclear envelope defects, cytoplasmic protein aggregation, activation of the Nrf2/Keap1 redox pathway, and reductive stress. These defects reduced larval motility and caused death at the pupal stage. Patient-derived cardiomyocytes expressing mutant lamins showed nuclear envelope deformations. The Drosophila models allowed for genetic and pharmacological manipulations at the organismal level. Genetic interventions to increase autophagy, decrease Nrf2/Keap1 signaling, or lower reducing equivalents partially suppressed the lethality caused by mutant lamins. Moreover, treatment of flies with pamoic acid, a compound that inhibits the NADPH-producing malic enzyme, partially suppressed lethality. Taken together, these studies have identified multiple new factors as potential therapeutic targets for LMNA-associated muscular dystrophy.Gary S. CoombsJose L. Rios-MonterrosaShuping LaiQiang DaiAshley C. GollMargaret R. KettererMaria F. ValdesNnamdi UcheIvor J. BenjaminLori L. WallrathElsevierarticleDrosophilaLaminsMuscular dystrophyNuclear envelopeReductive stressMedicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102196- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Drosophila Lamins Muscular dystrophy Nuclear envelope Reductive stress Medicine (General) R5-920 Biology (General) QH301-705.5
spellingShingle	Drosophila Lamins Muscular dystrophy Nuclear envelope Reductive stress Medicine (General) R5-920 Biology (General) QH301-705.5 Gary S. Coombs Jose L. Rios-Monterrosa Shuping Lai Qiang Dai Ashley C. Goll Margaret R. Ketterer Maria F. Valdes Nnamdi Uche Ivor J. Benjamin Lori L. Wallrath Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
description	Mutations in the human LMNA gene cause a collection of diseases called laminopathies, which includes muscular dystrophy and dilated cardiomyopathy. The LMNA gene encodes lamins, filamentous proteins that form a meshwork on the inner side of the nuclear envelope. How mutant lamins cause muscle disease is not well understood, and treatment options are currently limited. To understand the pathological functions of mutant lamins so that therapies can be developed, we generated new Drosophila models and human iPS cell-derived cardiomyocytes. In the Drosophila models, muscle-specific expression of the mutant lamins caused nuclear envelope defects, cytoplasmic protein aggregation, activation of the Nrf2/Keap1 redox pathway, and reductive stress. These defects reduced larval motility and caused death at the pupal stage. Patient-derived cardiomyocytes expressing mutant lamins showed nuclear envelope deformations. The Drosophila models allowed for genetic and pharmacological manipulations at the organismal level. Genetic interventions to increase autophagy, decrease Nrf2/Keap1 signaling, or lower reducing equivalents partially suppressed the lethality caused by mutant lamins. Moreover, treatment of flies with pamoic acid, a compound that inhibits the NADPH-producing malic enzyme, partially suppressed lethality. Taken together, these studies have identified multiple new factors as potential therapeutic targets for LMNA-associated muscular dystrophy.
format	article
author	Gary S. Coombs Jose L. Rios-Monterrosa Shuping Lai Qiang Dai Ashley C. Goll Margaret R. Ketterer Maria F. Valdes Nnamdi Uche Ivor J. Benjamin Lori L. Wallrath
author_facet	Gary S. Coombs Jose L. Rios-Monterrosa Shuping Lai Qiang Dai Ashley C. Goll Margaret R. Ketterer Maria F. Valdes Nnamdi Uche Ivor J. Benjamin Lori L. Wallrath
author_sort	Gary S. Coombs
title	Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
title_short	Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
title_full	Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
title_fullStr	Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
title_full_unstemmed	Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
title_sort	modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/4c9bdf11cf72460381870a3509fc100a
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Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins

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