Crosstalk between Nurr1 and risk factors of Parkinson's disease and its regulation by Nurr1's ligands

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Abstract: Selective degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra and abnormal accumulation and aggregation of α-synuclein in Lewy bodies are hallmark pathological features of Parkinson’s disease (PD). Currently, available treatments are symptomatic and there is no treatment that can halt or slow down the disease progression. Based on extensive studies on transcriptional regulation of mDA neurons from this and other laboratories, the orphan nuclear receptor Nurr1 (also known as NR4A2) has emerged as a master regulator of mDA neurons and a promising target for therapeutic development in PD. Although Nurr1 has been considered a ligand-independent, constitutively active transcription factor, we for the first time identified both synthetic (amodiaquine, chloroquine, and glafenine) and endogenous ligands (prostaglandin E1 (PGE1) and PGA1), which directly interact with the ligand binding domain (LBD) of Nurr1 and activate its transcription function with distinct mechanisms. Furthermore, we recently found that Nurr1 expression is significantly compromised by both prolonged exposure to neurotoxin and overexpression of α-synuclein. Based on these results, we hypothesize that Nurr1 is an “adopted” nuclear receptor and may have additional native ligands and that there is functional crosstalk between Nurr1 and PD risk factors. To address these hypotheses, we propose to investigate the following questions. First, we will address whether there exist additional endogenous ligands in the brain and whether better synthetic ligands can be generated, and we will investigate how these novel ligands regulate Nurr1’s transcriptional function. Second, we will investigate whether there is crosstalk between Nurr1 and PD risk factors and how Nurr1’s ligands regulate this crosstalk. Third, using in vivo models of PD, we will systematically investigate whether Nurr1’s synthetic and/or endogenous ligands can provide mechanism-based neuroprotection for eventual application as novel therapeutics for PD. If successful, these studies will advance our understanding of Nurr1’s function and regulation by its ligands in health and disease, and address whether Nurr1 can be a “druggable” target for PD.