PINK1 and MTF2 Modulators Synergize Cell Transplantation Therapy in Parkinsons Disease

Parkinsons Disease (PD), the second most prevalent neurodegenerative disease, has the key pathological feature of selective degeneration of dopaminergic neurons (DANs). Current cell therapy based remedy of PD centered on DAN transplantation, whether stem cell derived, or from fetal tissues, yet the possible dysfunction underlying in the microenvironment and non-neuronal mechanisms may impede this solution. The unresolved question is if microenvironment impairments and other non-cell-autonomous signaling may affect the healthy, transplanted DANs, triggering survival rate reduction. We hypothesized that non-neuronal mechanisms do exist thus specific drugs should be incorporated along with DANs during transplantation. Here we performed single cell RNA sequencing (scRNA-seq) analysis using Seurat and AI based package Monocle3 to confirm the existence of non-cell-autonomous signaling and revealed PINK1 and MTF2 as the main culprits through the comparison of initial differentiation dataset and long term transplantation dataset of transplanted DANs. Targeting PINK1, we identified the drug MTK458 and validated its effectiveness through AI based drug screening and molecular docking. Together, these findings supported MTK458 to be an effective co-transplant material designated for alleviating the abnormality in non-neuronal mechanisms or microenvironment.