Abstract
SummaryMutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.
Highlights
Many characteristics of normal aging appear to be accelerated in individuals with dominant mutations in the LMNA gene encoding Atype lamins (Ahmed, Ikram, Bibi & Mir, 2017; Apte, Stick &Radmacher, 2017; Cenni et al, 2017; Ikeda et al, 2016; Scaffidi & Misteli, 2006)
Summary Mutations in the human LMNA gene cause a collection of diseases known as laminopathies
We modeled human disease-causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart
Summary
Many characteristics of normal aging appear to be accelerated in individuals with dominant mutations in the LMNA gene encoding Atype lamins Studies in Drosophila demonstrated that mutant lamins, modeled after those that cause human disease, lead to cytoplasmic aggregation of nuclear envelope proteins and loss of redox homeostasis in larval body wall muscles (Dialynas et al, 2012, 2015). Consistent with these findings, human muscle biopsy tissues showed both cytoplasmic aggregation of nuclear envelope (NE) proteins and activation of the Nrf2/Keap-1 signaling pathway. Mutations in the human LMNA that cause dilated cardiomyopathy with conduction defects are often point mutations resulting in amino acid substitutions in residues conserved among species We modeled these mutations in the Drosophila Lamin C gene (hereafter referred as LamC) and assayed for effects on the fruit fly heart. The Drosophila models allowed for genetic tests of suppression and identified new potential therapeutic targets for individuals with cardiolaminopathy and other types of laminopathies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
