期刊
NEUROSCIENCE LETTERS
卷 759, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2021.136045
关键词
Parkinson's disease; Dopaminergic neurons; Nurr1; CREB; MPTP
资金
- National Natural Science Foundation of China [U1801681, 81771368, 32070959, 31871019]
- Key Realm RAMP
- D Program of Guangdong Province [2018B030337001]
- Guangdong Provincial Key Laboratory of Brain Function and Disease [2020B1212060024]
- Guangzhou Municipal Science and Technology Project [201804020008]
- National Key RAMP
- D Program of China [2018YFA0108302]
- Fundamental Research Funds for the Central Universities [19ykpy160]
Research has shown that in the mouse model of Parkinson's disease, CREB inactivation leads to the downregulation of Nurr1, while restoring CREB activity can rescue Nurr1 expression and provide neuroprotection.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Nurr1 (NR4A2), a nuclear receptor essential for the maintenance of midbrain dopaminergic neurons, is transcriptionally downregulated in both patients with PD and animal models and has been considered as a promising therapeutic target for neuroprotection in PD. However, the mechanism underlying Nurr1 downregulation during dopaminergic degeneration has not been fully elucidated. Here, we report that the pro-survival transcription factor CREB is constitutively bound to the Nurr1 promoter in the mouse SN. CREB inactivation by dephosphorylation at Ser133 occurred in parallel with Nurr1 downregulation in the MPTP mouse model of PD. Forced expression of VP16-CREB, a constitutively active mutant, rescued Nurr1 expression and showed prominent neuroprotection in MPTP-intoxicated mice. Collectively, our results demonstrate that Nurr1 downregulation in the MPTP-induced PD mouse model is caused by CREB inactivation, which may provide a new target for neuroprotective therapy in PD.
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