Although a number of genes have been identified as causes of familial PD, the majority of cases are sporadic and of unknown etiology (Farrer, 2006; Moore et al., 2005). An improved understanding of the causes of the more common forms of the disease will therefore be essential in developing broadly applicable treatment strategies. Here, we demonstrate that in addition to its essential roles in the development and maintenance of dopaminergic neurons, Nurr1 plays a previously unexpected role in protecting these neurons from inflammation-induced neurotoxicity. Several lines of evidence suggest that this role is due to its function as an inhibitor of inflammatory gene expression in microglia and astrocytes (Fig. 7A). First, these studies utilized a model system in which neurotoxicity was induced by LPS, which is not effectively sensed by neurons and does not directly cause neuronal death. Second, reduction of Nurr1 expression in the SN (primarily in microglia and astrocytes) did not in itself lead to reduction of TH+ neurons but did result in enhanced expression of inflammatory mediators and accelerated loss of TH+ neurons in response to LPS.
