The major motor disabilities of Parkinson's disease (PD) are associated with the progressive loss of dopaminergic neurons in the substantia nigra. The physiological changes and biochemical pathways involved in the selective demise of these neuronsare unclear. Survival of the dopaminergic precursor neurons during differentiation requires the function of NR4A2, a ligand independent nuclear receptor. Mutations in NR4A2 have been discovered in patients with familial PD. The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals.
Additionally, the mutations in NR4A2 affected the transcription of the gene encoding Tyrosine Hydroxylase (TH), an enzyme required for dopamine biosynthesis. Endogenous ligands that regulate RXR function as well as synthetic H gands that activate NR4A2-RXR heterodimers have been shown to mediate RXR ligand-induced signalling in neuronal cells. TheseRXR ligands require the presence of NR4A2 and increase the number of surviving dopaminergic cells and other neurons.
It is speculated that NR4A2, as a transcription factor, controls the expression of neuroprotective factors possibly by associating with RXR. In this proposal we aim to identify such factors. Since the number and the identity of the genes whose expression is controlled by NR4A2 and/or NR4A2/RXR heterodimers are unknown we propose to identify these genes and determine the function of the ones that mediate neuroprotective effects. In addition, we propose to clarify the transcriptional relationship of NR4A2 to the other genes that have been linked to familial PD including alpha-synuclein, parkin, DJ1, UCHL1 and PINK. The results of our experiments may reveal the factors that lead to the prevention or perhaps reversal of the major motor disabilities of PD by increasing dopaminergic cell survival.
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