Description
Laminopathies are a group of genetic disorders caused by dominant mutations in the human LMNA gene, which encodes the developmentally regulated A-type Lamins. Lamins are intermediate filaments proteins that line the inner nuclear membrane and provide structural support for the nucleus. Patients with Laminopathies exhibit a wide range of disorders including cardiac and skeletal muscle dysfunction, dysplasia, diabetes, and progeria. In particular, cardiomyopathy is the major cause of death in Laminopathy patients; however the underlying molecular mechanisms are not well understood. We generated Drosophila models to dissect the physiological and pathological roles of Lamins in cardiac function. Specifically, we generated flies that express the Drosophila Lamin C gene encoding amino acid substitutions (LamC R205W, G489V, A177P, V528P) that are analogous to those associated with cardiomyopathy in humans. Cardiac-specific expression of mutant LamC, but not the wild type, resulted in compromised cardiac function accompanied by cytoplasmic aggregation of Lamins, mislocalization of Nrf2 (CncC), disruption of the cytoskeleton and nuclear blebbing. In addition, expression of mutant LamC resulted in a shortened lifespan. We hypothesize that mutant Lamin and/or its cytoplasmic mislocalization triggers signaling pathways that alter cellular redox and metabolic homeostasis, resulting in cardiac muscle dysfunction. Using a combination of genetic, physiological, and biochemical analyses, we have shown that over-expression of Atg-1 and RNAi knock-down of Nrf2 (CncC) resulted in improved cardiac function, reduced cytoplasmic aggregation of Lamin and relocalization of Nrf2 (CncC) to the cytoplasm. Moreover, we have shown that simultaneous over-expression of Atg-1 and RNAi knock-down of Nrf2 (CncC) are required for complete suppression of the cardiac phenotypes and increased lifespan. We have also shown that overexpression of AMPK and its downstream targets (PGC-1alpha, 4E-BP) resulted in improved cardiac function, myofibril organization and reduced cytoplasmic aggregation of Lamin. These findings suggest pathways and targets that are potential avenues for therapy for Laminopathy patients.
