The secreted protein netrin-1 has diverse functions among which guidance and survival of neurons when bound to its dependence receptor DCC. In the absence of netrin-1, DCC is cleaved and actively triggers cell death in various contexts. DCC is highly present in a subset of mature neurons that typically degenerates in Parkinson’s disease, dopaminergic neurons of the substantia nigra. Besides, polymorphisms of DCC gene are associated with the disease. Thus, netrin-1 signalling might be implicated in Parkinson’s disease pathogenesis. Here we show, in various Parkinson’s disease models and samples from Parkinson’s disease patient brains, a reduction of netrin-1 levels associated with an increase of DCC cleavage and caspase activity. Specific deletion of netrin-1 in the substantia nigra induces DCC cleavage and leads to the loss of dopamine neurons and motor deficits in mice while intrastriatal injection of netrin-1 restores dopamine neurons and improves motor behaviour in rodent models of the disease. These results highlight the therapeutic potential of targeting netrin-1 signalling in Parkinson’s disease