Evaluating LINC Complex Disruption Across Physiologically Demanding States

Background

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex spans the nuclear envelope and enables force transmission from the cytoskeleton to the nucleus. Lamins are intermediate filament proteins that form the nuclear lamina which protect DNA from these transmitted forces. In a disease state, the LMNA mutation causes deletion or structural alteration of lamins A/C, which reduces the functionality of the nuclear lamina and increases the risk of nuclear rupture. These defects give rise to diseases such as dilated cardiomyopathy in cardiac tissue and muscular dystrophy in skeletal muscle. 

LINC complex disruption is a promising therapy for these diseases because it mechanically decouples the nucleus from the cytoskeleton. Although the nucleus remains structurally compromised due to defective lamins A/C, reduced force transmission lowers the risk of nuclear rupture. 

Motivation

LINC complex disruption is achieved by expressing a dominant negative protein (dnKASH) that competitively blocks the interaction of native LINC complex proteins within the nuclear envelope. Although this strategy has shown efficacy without pathology in sedentary mouse models, its performance under more physiologically demanding conditions remains unknown. 

Aim

Evaluate the safety and efficacy of LINC complex disruption in physiologically demanding conditions. 

Hypothesis

LINC complex disruption will remain safe and effective in mitigating laminopathy in physiologically demanding conditions.

Figure Reference

a. Méjat, A., & Misteli, T. (2010). LINC complexes in health and disease. Nucleus (Austin, Tex.), 1(1), 40–52. https://doi.org/10.4161/nucl.1.1.10530.