Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
PreviousNext
Research Articles, Neurobiology of Disease

CREB Inactivation by HDAC1/PP1γ Contributes to Dopaminergic Neurodegeneration in Parkinson's Disease

Xiaoyi Xu (许潇依), Xin He (何鑫), Zeyan Zhang (张泽彦), Yanyi Chen (陈彦伊), Junyu Li (黎俊宇), Shanshan Ma (马珊珊), Qiaoying Huang (黄巧莹) and Mingtao Li (黎明涛)
Journal of Neuroscience 1 June 2022, 42 (22) 4594-4604; DOI: https://doi.org/10.1523/JNEUROSCI.1419-21.2022
Xiaoyi Xu (许潇依)
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xin He (何鑫)
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zeyan Zhang (张泽彦)
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yanyi Chen (陈彦伊)
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Yanyi Chen (陈彦伊)
Junyu Li (黎俊宇)
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shanshan Ma (马珊珊)
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Qiaoying Huang (黄巧莹)
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mingtao Li (黎明涛)
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for Parkinson's disease (PD). In the nigral dopaminergic neurons of postmortem human PD brains, we found that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. CREB dephosphorylation correlated with decreased expression of NURR1, one of its target genes crucial for dopaminergic neuron survival, confirming that CREB function was impaired in nigral dopaminergic neurons in PD. An MPTP mouse model was used to further elucidate the mechanism underlying CREB dephosphorylation. Protein phosphatase 1γ (PP1γ), which dephosphorylates CREB, was constitutively associated with histone deacetylase 1 (HDAC1). HDAC1 promotes CREB Ser133 dephosphorylation via a stable interaction with PP1γ. We found that CREB interacted with the HDAC1/PP1γ complex during dopaminergic neurodegeneration. Importantly, increased CREB/HDAC1 interaction occurred in the nigral dopaminergic neurons of PD patients as demonstrated using a proximity ligation assay. Disrupting CREB/HDAC1 interaction via either overexpression of GAL4 M1, a CREB mutant, or administration of trichostatin A, a pan-HDAC inhibitor, restored the expression levels of phospho-CREB (Ser133) and NURR1, and protected nigral dopaminergic neurons in the MPTP-treated mouse brain. Collectively, our results demonstrated that HDAC1/PP1γ-mediated CREB inactivation contributed to dopaminergic neuronal degeneration. Disruption of CREB/HDAC1 interaction has the potential to be a new approach for PD therapy.

SIGNIFICANCE STATEMENT Parkinson's disease (PD) is the most common movement disorder attributed to the progressive loss of dopaminergic neurons in the substantia nigra. Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for PD. We found in nigral dopaminergic neurons of postmortem human PD brains that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. HDAC1, constitutively associated with PP1γ, interacted with CREB to mediate its dephosphorylation during dopaminergic neurodegeneration. Disrupting CREB/HDAC1 interaction restored CREB activity and protected nigral dopaminergic neurons in the MPTP mouse brains. This work suggests that disruption of the CREB/HDAC1 interaction to restore CREB activity may be a potential therapeutic approach in PD.

  • CREB
  • HDAC
  • neurodegeneration
  • Parkinson's disease
  • PP1

SfN exclusive license.

View Full Text

Member Log In

Log in using your username and password

Enter your Journal of Neuroscience username.
Enter the password that accompanies your username.
Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
Back to top

In this issue

The Journal of Neuroscience: 42 (22)
Journal of Neuroscience
Vol. 42, Issue 22
1 Jun 2022
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
CREB Inactivation by HDAC1/PP1γ Contributes to Dopaminergic Neurodegeneration in Parkinson's Disease
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
CREB Inactivation by HDAC1/PP1γ Contributes to Dopaminergic Neurodegeneration in Parkinson's Disease
Xiaoyi Xu (许潇依), Xin He (何鑫), Zeyan Zhang (张泽彦), Yanyi Chen (陈彦伊), Junyu Li (黎俊宇), Shanshan Ma (马珊珊), Qiaoying Huang (黄巧莹), Mingtao Li (黎明涛)
Journal of Neuroscience 1 June 2022, 42 (22) 4594-4604; DOI: 10.1523/JNEUROSCI.1419-21.2022

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
CREB Inactivation by HDAC1/PP1γ Contributes to Dopaminergic Neurodegeneration in Parkinson's Disease
Xiaoyi Xu (许潇依), Xin He (何鑫), Zeyan Zhang (张泽彦), Yanyi Chen (陈彦伊), Junyu Li (黎俊宇), Shanshan Ma (马珊珊), Qiaoying Huang (黄巧莹), Mingtao Li (黎明涛)
Journal of Neuroscience 1 June 2022, 42 (22) 4594-4604; DOI: 10.1523/JNEUROSCI.1419-21.2022
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Keywords

  • CREB
  • HDAC
  • neurodegeneration
  • Parkinson's disease
  • PP1

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

Research Articles

  • Muscarinic Acetylcholine M2 Receptors Regulate Lateral Habenula Neuron Activity and Control Cocaine Seeking Behavior
  • Sensorimotor Cortex GABA Moderates the Relationship between Physical Exertion and Assessments of Effort
  • Dual leucine zipper kinase regulates Dscam expression through a non-canonical function of the cytoplasmic poly(A)-binding protein
Show more Research Articles

Neurobiology of Disease

  • Muscarinic Acetylcholine M2 Receptors Regulate Lateral Habenula Neuron Activity and Control Cocaine Seeking Behavior
  • Sensorimotor Cortex GABA Moderates the Relationship between Physical Exertion and Assessments of Effort
  • Dual leucine zipper kinase regulates Dscam expression through a non-canonical function of the cytoplasmic poly(A)-binding protein
Show more Neurobiology of Disease
  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
(JNeurosci logo)
(SfN logo)

Copyright © 2022 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.