Generation and characterisation of hiPSC-derived sympathetic neurons carrying a PKP2 mutation

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterised by the loss of cardiomyocytes and fibrofatty myocardial replacement, which leads to arrhythmias and increases the risk of sudden cardiac death in young patients and athletes. Most cases are associated with mutations in the genes encoding desmosomal proteins, with Plakophilin-2 (PKP2) being the most prevalent. The observed correlation between physical and emotional stress and the onset of arrhythmias suggests a contributory role of sympathetic innervation. To investigate the impact of mutated desmosomal proteins on cardiac innervation, sympathetic neurons were differentiated from a patient-derived hiPSC line carrying a heterozygous mutation in the PKP2 gene and the isogenic control line. The obtained neurons were subsequently characterised morphologically by immunofluorescence and functionally by micro-electrode array (MEA) recordings to understand whether the altered expression of desmosomal proteins is sufficient to impair sympathetic neurons' function. In this work, I demonstrate that PKP2-mutated sympathetic neurons seem to exhibit increased electrical activity and display longer axons with more stable microtubules compared to the isogenic control cells. These preliminary data support the hypothesis that PKP2 mutations per se can influence the morphology and function of sympathetic neurons.