2. Academic Validation
  3. Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity

Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity

  • Cell Death Discov. 2022 May 20;8(1):267. doi: 10.1038/s41420-022-01063-9.
Qianqian Cao  # 1 2,  Qiuming Zou  # 3,  Xin Zhao  # 1,  Yimin Zhang  # 1,  Youge Qu 4,  Nanbu Wang 5,  Shigeo Murayama 6,  Qi Qi 3,  Kenji Hashimoto 7,  Song Lin 8,  Ji-Chun Zhang 9
Affiliations

Affiliations

  • 1 Department of Physiology, School of Medicine, Jinan University, 510632, Guangzhou, China.
  • 2 Department of Nuclear Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China.
  • 3 Department of Pharmacology, School of Medicine, Jinan University, 510632, Guangzhou, China.
  • 4 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
  • 5 The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 510632, Guangzhou, China.
  • 6 Department of Neuropathology (Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Tokyo, 173-0015, Japan.
  • 7 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. hashimoto@faculty.chiba-u.jp.
  • 8 Department of Physiology, School of Medicine, Jinan University, 510632, Guangzhou, China. linsong@jnu.edu.cn.
  • 9 Department of Physiology, School of Medicine, Jinan University, 510632, Guangzhou, China. jczhang@jnu.edu.cn.
  • # Contributed equally.
PMID: 35595779 DOI: 10.1038/s41420-022-01063-9
Abstract

Mounting evidence suggests the key role of brain-derived neurotrophic factor (BDNF) in the dopaminergic neurotoxicity of Parkinson's disease (PD). Activation of NF-E2-related factor-2 (Nrf2) and inhibition of methyl CpG-binding protein 2 (MeCP2) can regulate BDNF upregulation. However, the regulation of BDNF by Nrf2 and MeCP2 in the PD pathogenesis has not been reported. Here, we revealed that Nrf2/MeCP2 coordinately regulated BDNF transcription, reversing the decreased levels of BDNF expression in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Repeated administration of sulforaphane (SFN, an Nrf2 activator) attenuated dopaminergic neurotoxicity in MPTP-treated mice through activation of BDNF and suppression of MeCP2 expression. Furthermore, intracerebroventricular injection of MeCP2-HDO, a DNA/RNA heteroduplex oligonucleotide (HDO) silencing MeCP2 expression, ameliorated dopaminergic neurotoxicity in MPTP-treated mice via activation of Nrf2 and BDNF expression. Moreover, we found decreased levels of Nrf2 and BDNF, and increased levels of MeCP2 protein expression in the striatum of patients with dementia with Lewy bodies (DLB). Interesting, there were correlations between BDNF and Nrf2 (or MeCP2) expression in the striatum from DLB patients. Therefore, it is likely that the activation of BDNF transcription by activation of Nrf2 and/or suppression of MeCP2 could be a new therapeutic approach for PD.

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