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 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.

The ABCF gene family facilitates disaggregation during animal development.

Protein aggregation, once believed to be a harbinger and/or consequence of stress, age, and pathological conditions, is emerging as a novel concept in cellular regulation. Normal versus pathological aggregation may be distinguished by the capacity of cells to regulate the formation, modification, and dissolution of aggregates. We find that Caenorhabditis elegans aggregates are observed in large cells/blastomeres (oocytes, embryos) and in smaller, further differentiated cells (primordial germ cells), and their analysis using cell biological and genetic tools is straightforward. These observations are consistent with the hypothesis that aggregates are involved in normal development. Using cross-platform analysis in Saccharomyces cerevisiae, C. elegans, and Xenopus laevis, we present studies identifying a novel disaggregase family encoded by animal genomes and expressed embryonically. Our initial analysis of yeast Arb1/Abcf2 in disaggregation and animal ABCF proteins in embryogenesis is consistent with the possibility that members of the ABCF gene family may encode disaggregases needed for aggregate processing during the earliest stages of animal development.