AbstractEstrogens are considered neurotrophic for dopamine neurons. Parkinson’s disease is more frequent in males than in females, and more prevalent in females with short reproductive life. Estrogens are neuroprotective against neurotoxic agents for dopamine neurons in vivo and in vitro. Here, we have investigated the role of estrogens in wild‐type (WT) and parkin null mice (PK−/−). WT mice present sexual dimorphisms in neuroprotective mechanisms (Bcl‐2/Bax, chaperones, and GSH), but some of these inter‐sex differences disappear in PK−/−. Tyrosine hydroxylase (TH) protein and TH+ cells decreased earlier and more severely in female than in male PK−/− mice. Neuronal cultures from midbrain of WT and PK−/− mice were treated with estradiol from 10 min to 48 h. Short‐term treatments activated the mitogen‐activated protein kinase pathway of WT and PK−/− neurons and the phosphatidylinositol 3′‐kinase/AKT/glycogen synthase kinase‐3 pathway of WT but not of PK−/− cultures. Long‐term treatments with estradiol increased the number of TH+ neurons, the TH expression, and the extension of neurites, and decreased the level of apoptosis, the expression of glial fibrillary acidic protein, and the number of microglial cells in WT but not in PK−/− cultures. The levels of estrogen receptor‐α were elevated in midbrain cultures and in the striatum of adult PK−/− male mice, suggesting that suppression of parkin changes the estrogen receptor‐α turnover. From our data, it appears that parkin participates in the cellular estrogen response which could be of interest in the management of parkin‐related Parkinson’s disease patients.