Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins. Redox Biol 2021 Nov 25;48:102196
Date
12/07/2021Pubmed ID
34872044Pubmed Central ID
PMC8646998DOI
10.1016/j.redox.2021.102196Scopus ID
2-s2.0-85120438753 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
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.
Author List
Coombs GS, Rios-Monterrosa JL, Lai S, Dai Q, Goll AC, Ketterer MR, Valdes MF, Uche N, Benjamin IJ, Wallrath LLAuthors
Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of WisconsinQiang Dai Research Scientist I in the Medicine department at Medical College of Wisconsin
