Protein quality control and tubulin signature in inherited cardiomyopathies

This thesis is about cardiomyopathies. These are diseases of the heart muscle (myocardium) in which the structure of the muscle tissue changes and performance is lost. The affected heart can no longer carry enough blood through the circulation and heart failure develops. There are three main forms: dilated (DCM), hypertrophic (HCM), and restrictive (RCM) cardiomyopathy. All three forms of cardiomyopathy can be genetic, which means that the disease can be caused by a hereditary predisposition (mutation in the DNA). In this work, we investigated these genetically inherited cases and focused on mutations that affect the heart muscle. Even in patients with the genetically identical variant, the course of the disease varies greatly from person to person. Therefore, it is paramount to identify additional disease triggers to better understand the underlying pathomechanism. We used cellular, genetic, and clinical data from well-researched patient cohorts and several cardiomyopathies model systems to investigate potential triggers. In this work, we focused on the protein quality control system (PQC) and the microtubule network. The PQC system is a cellular defense mechanism responsible for maintaining a functioning proteome. Defective or mutated proteins are recognized by heat shock proteins (HSPs) and if repair is not possible, the mutated proteins are broken down. Only limited research has been done on the role of PQC in inherited cardiomyopathies. Microtubules are small, tubular protein complexes composed of alpha- and beta-tubulin. They form the basis for the cytoskeleton and thus give the cell a certain mechanical stability. The microtubule network is known to remodel in various diseases. In summary, this thesis investigated the PQC and microtubule signature in hereditary cardiomyopathies. Potential associations were identified and the use of dynamic model systems in future studies is recommended to better understand the influence of the PQC system and the restructuring of the microtubule network on the pathomechanism in cardiomyopathies.