Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic based cardiac disease, which is characterized by ventricular dysfunction, fibrofatty accumulation, and ventricular arrhythmias culminating in sudden death. ARVC has been termed a disease of the desmosome, a type of cell-cell junction, as human genetic studies have identified mutations in components of the desmosome as causal for the disease. Desmosomal protein loss is considered a molecular hallmark of ARVC, however, the mechanisms controlling desmosomal protein degradation that may impact cardiac disease remain uncharacterized. In this dissertation, I aim to better understand the mechanisms linking desmosomal biology to development of disease features of ARVC.

In my studies, I have identified a novel link between protein degradation defects and cardiac arrhythmias in ARVC through identification of a novel cardiac desmosomal protein. I performed a yeast-2-hybrid screen using the N-terminus of the desmosomal protein, desmoplakin (DSP) and identified a novel interaction with the autophagy associated protein synaptosomal associated protein 29 kDa (SNAP29). To determine the role of SNAP29 in the heart, I generated a novel cardiac specific SNAP29 knockout (SNAP29-cKO) mouse by crossing a SNAP29-floxed mouse line with the cardiac specific XMLC2-Cre mouse line. Characterization of this line revealed spontaneous and inducible ventricular arrhythmias and lipid droplet accumulation. These defects were associated with specific loss of select desmosomal and gap junction proteins and accumulation of autophagosome-like and autolysosome-like structures specifically at the cardiomyocyte cell-cell junctions. In vitro studies revealed that autophagy is activated and targets DSP in the absence of SNAP29. In a DSP-deficient (DSP-cKO) mouse model of ARVC, I observed autophagy defects characteristic of SNAP29 deficiency, suggesting that SNAP29-mediated autophagy may underlie ARVC. In a SNAP29-null mouse model of the human brain and skin disease CEDNIK, I observed characteristic desmosomal, gap junction, autophagy, and electrical defects in neonatal hearts as observed in SNAP29-cKO and DSP-cKO mouse hearts, suggesting cardiac desmosomal defects may underlie CEDNIK.

In conclusion, my doctoral studies provide evidence for a novel interaction between SNAP29 and DSP and a new mechanism regulating cardiac rhythm wherein cardiomyocyte SNAP29 protects desmosomes from targeted protein degradation via autophagy to restrict ventricular arrhythmias.