ADROSOPHILA MODEL OF LAMIN-ASSOCIATED CARDIOMYOPATHY REVEALS ALTERED REDOX HOMEOSTASIS AND SHORTENED LIFE SPAN
Mastaneh Nikravesh1, Girish Melkani1, Sreehari Kalvakuri1, Jessica M. Ponce2, Dylan A. Thiemann2, Grant H. Young2, Lori L. Wallrath2.Rolf Bodmer1.
1Sanford Burnham Medical Research Institute, La Jolla, CA, 2University of Iowa, Iowa City, IA.
Laminopathies are a group of genetic disorders caused by mutations in the LMNA gene encoding A-type lamins, intermediate filaments that line the inside of the nuclear envelope. Patients with laminopathies exhibit a spectrum of phenotypes including cardiac and skeletal muscle dysfunction, dysplasia, diabetes, and progeria. Among these, dilated cardiomyopathy (DCM) is a major cause of death, yet the underlying mechanisms of pathology remain unknown. We have developed a Drosophila model to functionally dissect the roles of lamins in the heart. We investigated laminopathy-associated cardiac dysfunction by expressing Drosophila lamin (LamC), possessing mutations analogous to those that cause human disease, in the heart. Heart-specific expression of wild-type LamC caused no observable phenotypes. In contrast, heart-specific expression of mutant LamC caused conduction defects accompanied by either restricted or dilated cardiomyopathy, depending on the specific mutation. Expression of mutant LamC in the heart also caused nuclear envelope deformation, cytoplasmic aggregation of lamins, age-dependent altered redox homeostasis, and a shortened life span. Currently, we are investigating candidate genes and pathways that are able to modulate these pathological phenotypes, which will provide potential avenues for therapeutic intervention.