Here, using three different in vitro models of DA toxicity (i.e.: serum deprivation, SD, 6-OHDA and MPP+ exposure) in purified neurons and astrocyte-neuron co-culture paradigms, using pharmacological antagonism or RNA silencing along with functional studies in both intact and SN lesioned mice, we highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons with potential implications for drug design or drug action in PD. Here, FZD1 is linked to Parkinson disease.