Impaired neurogenesis and synaptogenesis in iPSC-derived Parkinson’s patient cortical neurons with D620N VPS35 mutation

Presynaptic dysfunction is an important early process in the pathophysiology of Parkinson’s disease (PD) that drives disease progression. To gain insight into the intrinsic synapse impairment in PD, we performed comprehensive electrophysiological and morphological analysis of iPSC-derived cortical neurons derived from PD patients with the VPS35-D620N mutation. Our findings reveal significant impairment in neurogenesis and synaptogenesis within individual patient neurons, culminating to synaptic dysfunction even in the absence of neuronal interactions. The neurons exhibited significantly reduced synaptic responsiveness, fewer synapse and decreased dendritic length and complexity. Thus, the VPS35-D620N mutation in human cortical neurons independently can cause pathophysiology via synaptic dysfunction. Our study highlights the urgent need to develop disease-modifying therapies aimed at preserving synaptic function in PD.