Date Published: March 25, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Shruti Bhide, Adriana S. Trujillo, Maureen T. O’Connor, Grant H. Young, Diane E. Cryderman, Sahaana Chandran, Mastaneh Nikravesh, Lori L. Wallrath, Girish C. Melkani.
Mutations 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.
Many characteristics of normal aging appear to be accelerated in individuals with dominant mutations in the LMNA gene encoding A‐type lamins (Ahmed, Ikram, Bibi & Mir, 2017; Apte, Stick & Radmacher, 2017; Cenni et al., 2017; Ikeda et al., 2016; Scaffidi & Misteli, 2006). These include cardiac diseases with a broad range of arrhythmic disturbances, left ventricle dysfunction, and heart failure that show increasing penetrance with age (Captur et al., 2017; Liang, Grogan & Ackerman, 2016). To gain insights into how to delay the onset and/or prevent these cardiac defects during aging, a greater understanding of the molecular basis of the pathology is needed.
Mutations in the human LMNA gene are associated with a collection of diseases called laminopathies in which the most common manifestation is progressive cardiac disease (Brayson & Shanahan, 2017; Heller et al., 2017; Marian, 2017; Naetar, Ferraioli & Foisner, 2017). We have generated Drosophila melanogaster models of age‐dependent cardiac dysfunction. In these models, mutations synonymous with those causing disease in humans were introduced into Drosophila LamC. Cardiac‐specific expression of mutant LamC resulted in (1) cardiac contractility, conduction, and physiological defects, (2) abnormal nuclear envelope morphology, (3) cytoplasmic LamC aggregation, (4) nuclear enrichment of the redox transcriptional regulator CncC (mammalian Nrf2), (5) and upregulation of autophagy cargo receptor Ref(2)P (mammalian p62) (Figures 1, 2, 3, 4, S3). These cardiac defects were enhanced with age (Figures 2 and S2) and accompanied by increased adipose tissue in the adult fat bodies (Figure 4f) and a shortened lifespan (Figure 1d, e).
Due to space limitation, experimental procedures are described in the Supplementary section.
GCM and LLW designed the project, conducted experiments, evaluated data, and prepared the manuscript; SB, AST, MTO, GHY, DEC, SC, and MN conducted experiments and evaluated data. All authors have reviewed the manuscript.