Netrin‐1 and its receptor DCC modulate survival and death of dopamine neurons and Parkinson's disease features.

The netrin‐1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of netrin‐1 and DCC is maintained in the adult brain, little is known about their role in mature neurons. Notably, netrin‐1 is highly expressed in the adult substantia nigra, leading us to investigate a role of the netrin‐1/DCC pair in adult nigral neuron fate. Here, we show that silencing netrin‐1 in the adult substantia nigra of mice induces DCC cleavage and a significant loss of dopamine neurons, resulting in motor deficits. Because loss of adult dopamine neurons and motor impairments are features of Parkinson's disease (PD), we studied the potential impact of netrin‐1 in different animal models of PD. We demonstrate that both overexpression of netrin‐1 and brain administration of recombinant netrin‐1 are neuroprotective and neurorestorative in mouse and rat models of PD. Of interest, we observed that netrin‐1 levels are significantly reduced in PD patient brain samples. These results highlight the key role of netrin‐1 in adult dopamine neuron fate, and the therapeutic potential of targeting netrin‐1 signaling in PD. SYNOPSIS: This study shows, using various in vivo approaches, a novel role for netrin‐1 as a key regulator of adult nigral dopamine neuron maintenance and highlights the therapeutic potential of targeting netrin‐1 signalling in Parkinson's disease. Netrin‐1 is required for the maintenance of adult dopamine neurons in the substantia nigraLoss of netrin‐1 in the substantia nigra induces receptor cleavage and apoptotic cell death of dopamine neuronsNetrin‐1 is protective and neurorestorative in various models of Parkinson's disease [ABSTRACT FROM AUTHOR]