Nur(R1)turing a Notion on the Etiopathogenesis of Parkinson’s Disease

Abstract

The canonical histopathological feature of Parkinson’s disease (PD) is the loss of dopaminergic neurons in the ventral midbrain. Although the common sporadic/idiopathic form of PD most often presents clinically at around 60 years of age when the levels of striatal dopamine and numbers of ventral dopaminergic neurons are posited to have declined by 80 and 60%, respectively, the temporal pattern of injury to these vulnerable cells is unknown. The conventional view is that PD results from an accelerated age-related loss of dopamine neurons. However, an alternative hypothesis is that dopamine neuron loss is a developmental phenomenon. What evidence might support this alternative view? Apart from the rare familial forms, wherein loss or gain of function mutations in single genes convey highly penetrant PD, sporadic disease is genetically complex and may have other contributory non-genetic components. Epidemiologic and twin studies have strongly implicated gene–environmental interaction as a pathogenic dyad in the etiology of PD. Among the most attractive candidates that may connect the environment to inherited vulnerability is the nuclear receptor, Nurr1. Encoding an orphan transcription factor that is expressed at high levels within discrete regions of the developing and adult mammalian brain, Nurr1 is essential for the formation of ventral midbrain dopamine neurons. Given the absence of a known lipophilic small molecule regulator and established transcriptional role in the formation of the definitive dopaminergic phenotype, Nurr1 represents an intriguing molecule to explore in the context of sporadic PD as a developmental disorder. The study described herein addresses two features of Nurr1 biology that provide plausibility for this hypothesis. First is the description of Nurr1 regulation of a potent dopaminergic neuronal trophic factor, vasoactive intestinal peptide (VIP), and second is the identification of a protein, termed Nurr1 interacting protein (NuIP) that appears to link upstream signaling pathways in the regulation of Nurr1 transcriptional activity.