An imbalance of netrin-1 and DCC during nigral degeneration in experimental models and patients with Parkinson's disease

Abstract Multiple guidance cues, such as netrin-1 (NTN-1)/deleted in colorectal carcinoma (DCC), control the guidance of axons and help establish functional neural circuits during development. However, the function of these guidance molecules in the adult brain, particularly during the neurodegenerative process, is unclear. NTN-1 and its receptor DCC play a critical role in the development and function of the midbrain dopamine circuitry. To access the alterations of NTN-1 and DCC during the onset and progression of PD, we first established two subacute and one chronic PD model and found that the imbalance of NTN-1 and DCC was a common feature of nigral DA neuron injury in the early stages of neurodegeneration. Moreover, we investigated the relationship between the NTN-1/DCC pathway and cell death in SH-SY5Y cells. MPP + inhibited NTN-1 expression and increased DCC expression in both a concentration and time-dependent manner, accompanied by reduced phosphorylation levels of FAK and Src. We further discovered a significant decrease in plasma NTN-1 levels and a positive correlation with UPDRS scores in PD patients. Our findings confirmed the imbalance of NTN-1/DCC signaling during nigral degeneration in experimental PD models and found for the first time a correlation of plasma NTN-1 with PD symptoms in patients.