Objective: The objective of our study is to determine if Nurr1 gene, a transcription factor essential for dopamine (DA) neuron development and survival, is a risk factor for Parkinson’s disease (PD), and its potential role in the pathogenesis and therapy of this disease.

Background: PD is the second most common neurodegenerative disease in adult, mainly manifesting movement disorder symptoms. The loss of DA neurons in the substantia nigra (SN) is the pathological hallmark of PD. Although many PD related genes and environmental factors have been identified, the mechanisms underlying the relative specific loss of DA neurons in PD are still poorly understood. Previously we have documented that Nurr1 is a critical gene regulating DA neuron differentiation and survival. This study is a continue investigation to determine the role and mechanism of Nurr1 in PD.

Methods: (1) We established two conditional knock-out Nurr1 mice models in DA neurons and microglia, and determined the animal’s movement behaviorals, nigral-striatal DA neuron pathologies, and quantitative measurements of Nurr1 down-stream genes/proteins expressions, Nurr1-α-synuclei interaction, and microglia activation and inflammation molecules in the SN. (2) We measured the expression levels of Nurr1 and several its down-stream genes in peripheral blood of over 700 PD patients’ compared with 830 healthy controls and 580 various neurological disease controls using real-time PCR. In addition, we also assessed several inflammation molecules in patients’ plasma using multi-ELISA assays.

Results: We have found that down-regulation of Nurr1 can cause DA neuron degeneration, decreased axonal guidance gene TopIIB, increase α-synuclein expression, and induce glia-mediated inflammation and neuronal injury. In addition, we documented that Nurr1 level was significantly lower, wherase inflammation molecules TNF-α, IL1β, IL-4, IL-6 and IL-10 were significantly higher in the peripheral blood of PD patients vs healthy and disease controls. The changes in Nurr1 expression and inflammation molecules were closely correlated with the disease progression. Moreover, we identified several small molecules acting on Nurr1 transcription site that can enhance DA synthesis and increase the survival of DA neurons in several in vitro and in vivo models of PD.

Conclusions: Nurr1 gene is a risk factor for PD, and we believe that Nurr1 may play an important role in the pathogenesis of PD and molecules targeting Nurr1 gene is a potential therapy for PD.

References: 1. Jankovic J, Chen S, Le W. (2005) Role of Nurr1 in dopamine neuron development and Parkinson disease. Progress in Neurobiol. 77:128-138.58. Le W, Chen S, Jankovic J. (2009) Etiopathogenesis of Parkinson disease: a new beginning? Neuroscientists 15:28-34 78. 2. Peng C, Aron L, Klein R, Li M, Wurst W, Prakash N, Le W. (2011) Pitx3 is a critical mediator of GDNF-induced BDNF expression in nigrostriatal dopaminergic neurons. J Neurosci. 31(36):12802-15.90. 3. Zhang LF, Le W*, Xie W, Dani J. (2012) Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson’s disease. Neurobio Aging. 33(5):1001.e7-16.86. 4. Liu H, Wei L, Tao Q, Deng H, Ming M, Xu P, Le W. (2012) Decreased NURR1 and PITX3 gene expression in Chinese patients with Parkinson’s disease. Eur J Neurol. 19(6):870-5. 5. Heng X, Jin G, Zhang X, Yang D, Zhu M, Fu S, Li X, Le W. (2012) Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neurons. Mol Neurodegener. 7:4-15. 6. Liu H, Wei L, Tao Q, Deng H, Ming M, Xu P, Le W. (2012) Decreased NURR1 and PITX3 gene expression in Chinese patients with Parkinson’s disease. Eur J Neurol. 19(6):870-5. 7. Heng X, Jin G, Zhang X, Yang D, Zhu M, Fu S, Li X, Le W. (2012) Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neurons. Mol Neurodegener. 7:4-15. 8. Yang D, Li T, Wang Y, Tang Y, Cui H, Tang Y, Zhang X, Chen D, Shen N, Le W. (2012) miR-132 regulates the differentiation of dopamine neurons by directly targeting Nurr1 expression. J Cell Sci. 125 (Pt 7):1673-82.130. 9. Dong J, Li S, Mo JL, Le W. (2016) Nurr1-based therapies for Parkinson’s disease. CNS Neuroscience & Therapeutics. 2016, Mar. 12 [Epub ahead of print].

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nurr1-gene-a-new-research-target-for-parkinsons-disease/