Selective Cav1.3 inhibition promotes survival of transplanted dopaminergic neurons via the CaMKII-p65-p53 pathway

Poor survival of transplanted midbrain dopaminergic neurons (mDANs) remains a key barrier for stem cell-based Parkinson's disease (PD) therapy. Cav1.3-containing L-type calcium channel blockers have been shown to prevent native mDAN loss in PD animal models and patients. Here, we aim to investigate whether they also enhance the post-transplant survival of stem cell-derived mDANs. We found that Cav1.3 is highly expressed in human embryonic stem cell-derived mDANs. Cav1.3 inhibitors including isradipine and cp-PYT significantly reduced apoptosis and improved mDAN survival in both interferon gamma (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-induced inflammatory models, as well as in the 6-OHDA-induced toxic model in vitro. Mechanistically, their protective effects are mediated through suppressing the CaMKII-p65-p53 signaling pathway. Moreover, we showed that cp-PYT treatment enhanced mDAN survival while reducing mature graft volume post-transplantation. Therefore, Cav1.3 inhibition may represent a clinically relevant strategy to enhance the survival of human pluripotent stem cell (hPSC)-derived mDANs in cell therapy for PD.