Related Experiment Video
Updated: May 12, 2026
Validation of a Mouse Model to Disrupt LINC Complexes in a Cell-specific Manner
Published on: December 10, 2015
Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA
Kunal Sikder1, Elizabeth Phillips1, Zhijiu Zhong2
1Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia PA, USA.
Insights
Mutations in the lamin A/C gene (LMNA) cause heart disease. This study reveals that perinuclear stress responses, including Golgi and autophagy disruption, drive LMNA cardiomyopathy development in mice.
Area of Science:
- Cardiovascular Biology
- Cellular Biology
- Genetics
Background:
- Mutations in the LMNA gene cause laminopathies, frequently affecting the heart.
- The precise mechanisms driving LMNA-associated cardiac dysfunction are not fully understood.
Purpose of the Study:
- To investigate the cellular and molecular pathogenesis of LMNA-related cardiomyopathy.
- To identify therapeutic targets for LMNA-associated heart disease.
Main Methods:
- Conditional cardiomyocyte-specific Lmna deletion in adult mice.
- Translatome profiling to analyze gene expression changes.
- Assessment of nuclear, Golgi, and autophagy integrity.
- Evaluation of therapeutic interventions targeting stress pathways.
Main Results:
- Mice with cardiomyocyte-specific Lmna deletion rapidly developed cardiomyopathy and pathological remodeling.
- Nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress were observed prior to cardiac dysfunction.
- Translatome profiling revealed MED25 activation, linked to Golgi stress.
- Autophagy disruption was evident and could be mimicked by Golgi disruption.
- Modulators of autophagy or ER stress administration delayed cardiac dysfunction and improved survival.
Conclusions:
- Stress responses originating from the perinuclear space, involving Golgi and autophagy, are critical in LMNA cardiomyopathy pathogenesis.
- Targeting autophagy and ER stress pathways shows therapeutic potential for LMNA-related heart conditions.
Abstract:
Mutations in the LMNA gene encoding lamins A/C cause an array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis underlying cardiac dysfunction remains elusive. Using a novel conditional deletion model capable of translatome profiling, we observed that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Before cardiac dysfunction, Lmna-deleted cardiomyocytes displayed nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation. Translatome profiling identified MED25 activation, a transcriptional cofactor that regulates Golgi stress. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the Golgi. Systemic administration of modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the LMNA cardiomyopathy development.
Related Concept Videos
01:08Nucleotide Excision Repair
01:26Cross-bridge Cycle
01:38Nucleotide Excision Repair
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
01:28Disorders of the Nervous Tissue
Homeostatic Imbalances:
Alzheimer's disease manifests as a gradual decline in memory and cognitive abilities, attributed to the buildup of amyloid plaques and neurofibrillary tangles in the brain.
Parkinson's disease arises from the...
01:21Myocarditis I: Introduction
01:16Cellular Injury IV: Necrosis