Understanding the role of alpha-actinin in cardiac disease: from molecules to mice

In the heart and skeletal muscle, the Z-disc is a crucial structure to anchor thin filaments of the contractile units. Moreover, the Z-disc is recognised as a signalling hub, sensing and responding to changes in the environment. Within the Z-disc, the protein alpha-actinin crosslinks actin filaments. Missense variants in alpha-actinin have been reported to cause cardiac disease (Hypertrophic Cardiomyopathy). However, the underlying mechanisms of how such mutations cause disease are unknown. This project will investigate the consequences of a cardiac-disease causing alpha-actinin missense variant. It is expected that small changes in the protein structure lead to disturbances of contractility and protein turnover, ultimately compromising heart function. This interdisciplinary project will address the pathogenic mechanisms by exploiting biophysical and structural approaches, in combination with the investigations of an induced pluripotent stem cell derived cardiomyocyte model (both in 2D and 3D) and High-resolution Episcopic Microscopy in an in vivo model. Collectively, these studies will identify novel signalling functions of alpha-actinin, define how they are impaired in the presence of the disease-causing variant and will inform development of novel therapies targeting cardiomyopathies.