Gdnf: a Key Player in Neuron–glia Crosstalk and Survival of Nigrostriatal Dopaminergic Neurons

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons of the nigrostriatal pathway that degenerate in Parkinson’s disease (PD). In animal models of PD, GDNF delivery has been shown to both protect dopaminergic neurons against toxin-induced injury and to rescue damaged neurons, promoting recovery of the motor deficit. GDNF may act both as a target-derived neurotrophic factor in the striatum, and as a local neurotrophic factor at the level of neuronal cell bodies in the substantia nigra. The neuroprotective and regenerative effects of GDNF are mediated by increases in the activity of antioxidant enzymes and induction of antiapoptotic proteins and cell adhesion molecules. In addition, GDNF stimulates dopaminergic neurotransmission by increasing dopamine biosynthesis and neuronal excitability. In the normal adult brain, GDNF is expressed mainly by neuronal cells but, upon injury, both astrocytes and microglial cells express GDNF. How neuronal damage signals glial cells to upregulate GDNF is being uncovered. Dopamine agonists, interleukin-1β (IL-1β) and estrogen have been shown to modulate GDNF expression by astrocytes and/or microglial cells. GDNF produced by activated microglial cells is involved in the axonal growth and sprouting of damaged neurons. Moreover, GDNF can modulate the migration, adhesion and phagocytic activity of microglia. The intercellular messengers involved in the crosstalk between dopaminergic neurons, astrocytes and microglia are potential targets for PD therapies aimed at upregulating the endogenous expression of GDNF.