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.

Automated summary

The netrin-1/DCC ligand/receptor pair plays key roles in CNS development, and although they are expressed in the adult brain, their function in mature neurons is not well understood. Research shows that netrin-1 plays a critical role in the fate of adult dopamine neurons, and targeting netrin-1 signaling may have therapeutic potential in Parkinson's disease. Studies in animal models suggest that overexpression of netrin-1 or administration of recombinant netrin-1 can be neuroprotective and neurorestorative in PD.