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

Neurosci Lett. 2021 Aug 10:759:136045. doi: 10.1016/j.neulet.2021.136045. Epub 2021 Jun 11.

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.

Keywords: CREB; Dopaminergic neurons; MPTP; Nurr1; Parkinson’s disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Down-Regulation
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
  • Parkinsonian Disorders / metabolism*
  • Substantia Nigra / metabolism

Substances

  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Nr4a2 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 2