Significance Netrin1 is an important molecule for dopaminergic neuronal survival and axon guidance. The Hippo/MST1/2 pathway plays a critical role in restricting tissue growth in adults and modulating cell proliferation, differentiation, and migration in developing organs as well as in the brain. Here, we demonstrate that Netrin1 is deficient in PD patient’s brain that activates Hippo/MST1 kinase, which selectively binds and phosphorylates netrin receptor UNC5B on T428 residue, promoting its apoptotic activation and dopaminergic neuronal loss. Hence, Netrin1 reduction acts as an extrinsic stimulus that triggers Hippo/MST1/YAP pathway activation, leading to dopaminergic neuronal loss in PD pathogenesis.