Nurr1 downregulation is caused by CREB inactivation in a Parkinson's disease mouse model.

Neuroscience Letters
Xiaoyi XuQiaoying Huang

Abstract

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.

References

Apr 11, 1997·Science·R H ZetterströmT Perlmann
Jul 8, 1997·Proceedings of the National Academy of Sciences of the United States of America·S HunotE C Hirsch
Apr 23, 2002·Nature Genetics·Theo MantamadiotisGünther Schütz
Dec 2, 2005·The Journal of Comparative Neurology·Yaping ChuJeffrey H Kordower
Apr 20, 2006·The Journal of Biological Chemistry·Elisabeth M ChalovichCharleen T Chu
May 23, 2006·Lancet Neurology·Lonneke M L de Lau, Monique M B Breteler
Nov 15, 2007·Proceedings of the National Academy of Sciences of the United States of America·Anamitra GhoshKalipada Pahan
Dec 18, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Banafsheh KadkhodaeiThomas Perlmann
Jun 23, 2010·Proceedings of the National Academy of Sciences of the United States of America·Nikolaos VolakakisThomas Perlmann
Nov 4, 2010·Journal of Neurochemistry·Kensuke SakamotoKarl Obrietan
Dec 12, 2012·Science Translational Medicine·Mickael DecressacAnders Björklund
Oct 16, 2013·Nature Reviews. Neurology·Mickael DecressacThomas Perlmann
Mar 12, 2015·EMBO Molecular Medicine·Sang-Min OhSang-Hun Lee
Mar 26, 2016·CNS Neuroscience & Therapeutics·Jie DongWei-Dong Le
Apr 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Kwang-Soo Kim
Nov 4, 2017·Trends in Neurosciences·Carlos A Saura, Jean-René Cardinaux
Feb 12, 2020·JAMA : the Journal of the American Medical Association·Melissa J Armstrong, Michael S Okun
Jun 2, 2020·Frontiers in Molecular Neuroscience·Congcong JiaWeidong Le
Jan 23, 2021·Experimental & Molecular Medicine·Yongwoo JangKwang-Soo Kim

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