The Parkinson’s disease associated Leucine-rich repeat kinase 2 affects expression of Transferrin receptor 1 and phosphorylation of key signaling proteins in human iPSC-derived dopaminergic neurons

Several variants in the Leucine-rich repeat kinase 2 ( LRRK2 ) gene account for familiar and sporadic late-onset Parkinson’s disease (PD). LRRK2 is a large, multifunctional kinase involved in different intracellular pathways crucial for homeostasis and cell survival. One of the poorly understood mechanisms of Parkinsonism is the iron accumulation in Substantia nigra pars compacta ( SNc ). Transferrin receptor 1 (TfR) plays a significant role for iron uptake into the cell. Here, we investigated the expression of TfR in human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (hDANs) generated from PD patients carrying the LRRK2 p.G2019S form and found dysregulated TfR levels. In addition, we found gene status depending variations of LRRK2 expression in differentiated hDANs, while neuronal progenitor cells (NPCs) did not display these changes. This suggests an unknown regulatory mechanism of LRRK2 expression during dopaminergic differentiation. Further investigations showed dysregulated phosphorylation of the PD-associated GSK-3β und the key signaling factor Akt.