AbstractAimsMultiple 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 during the neurodegenerative process is unclear.MethodsTo 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. Then, we investigated the relationship between the NTN‐1/DCC pathway and cell death in SH‐SY5Y cells. Finally, we conducted correlation studies between plasma NTN‐1 and parkinsonian symptoms in patients to understand how this pathway contributes to PD.ResultsWe found that the imbalance of NTN‐1 and DCC was a common feature of nigral DA neuron injury in PD mouse models. We investigated that MPP+ inhibited NTN‐1 expression and increased DCC expression in a concentration‐ and time‐dependent manner. We further discovered a significant decrease in plasma NTN‐1 levels and a positive correlation with UPDRS scores in PD patients.ConclusionOur 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.