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
Articles, Neurobiology of Disease

G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons

Laura A. Volpicelli-Daley, Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher, Austen J. Milnerwood, Vivek K. Unni, Warren D. Hirst, Zhenyu Yue, Hien T. Zhao, Kyle Fraser, Richard E. Kennedy and Andrew B. West
Journal of Neuroscience 13 July 2016, 36 (28) 7415-7427; DOI: https://doi.org/10.1523/JNEUROSCI.3642-15.2016
Laura A. Volpicelli-Daley
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Laura A. Volpicelli-Daley
Hisham Abdelmotilib
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hisham Abdelmotilib
Zhiyong Liu
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lindsay Stoyka
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
João Paulo Lima Daher
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Austen J. Milnerwood
2Centre for Applied Neurogenetics, Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3 Canada,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Austen J. Milnerwood
Vivek K. Unni
3Jungers Center for Neurosciences Research and Parkinson Center of Oregon, Department of Neurology, Oregon Health & Science University, Portland, Oregon 97239,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Warren D. Hirst
4Pfizer Neuroscience and Pain Research Unit, Cambridge, Massachusetts 02139,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zhenyu Yue
5Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hien T. Zhao
6Ionis Pharmaceuticals, Carlsbad, California 92010, and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kyle Fraser
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kyle Fraser
Richard E. Kennedy
7Comprehensive Center for Healthy Aging and Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Richard E. Kennedy
Andrew B. West
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294,
  • 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

This article has a correction. Please see:

  • Erratum: Volpicelli-Daley et al., “G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons” - January 12, 2022

Abstract

Pathologic inclusions define α-synucleinopathies that include Parkinson's disease (PD). The most common genetic cause of PD is the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity. However, the interaction between α-synuclein, LRRK2, and the formation of α-synuclein inclusions remains unclear. Here, we show that G2019S-LRRK2 expression, in both cultured neurons and dopaminergic neurons in the rat substantia nigra pars compact, increases the recruitment of endogenous α-synuclein into inclusions in response to α-synuclein fibril exposure. This results from the expression of mutant G2019S-LRRK2, as overexpression of WT-LRRK2 not only does not increase formation of inclusions but reduces their abundance. In addition, treatment of primary mouse neurons with LRRK2 kinase inhibitors, PF-06447475 and MLi-2, blocks G2019S-LRRK2 effects, suggesting that the G2019S-LRRK2 potentiation of inclusion formation depends on its kinase activity. Overexpression of G2019S-LRRK2 slightly increases, whereas WT-LRRK2 decreases, total levels of α-synuclein. Knockdown of total α-synuclein with potent antisense oligonucleotides substantially reduces inclusion formation in G2019S-LRRK2-expressing neurons, suggesting that LRRK2 influences α-synuclein inclusion formation by altering α-synuclein levels. These findings support the hypothesis that G2019S-LRRK2 may increase the progression of pathological α-synuclein inclusions after the initial formation of α-synuclein pathology by increasing a pool of α-synuclein that is more susceptible to forming inclusions.

SIGNIFICANCE STATEMENT α-Synuclein inclusions are found in the brains of patients with many different neurodegenerative diseases. Point mutation, duplication, or triplication of the α-synuclein gene can all cause Parkinson's disease (PD). The G2019S mutation in LRRK2 is the most common known genetic cause of PD. The interaction between G2019S-LRRK2 and α-synuclein may uncover new mechanisms and targets for neuroprotection. Here, we show that expression of G2019S-LRRK2 increases α-synuclein mobility and enhances aggregation of α-synuclein in primary cultured neurons and in dopaminergic neurons of the substantia nigra pars compacta, a susceptible brain region in PD. Potent LRRK2 kinase inhibitors, which are being developed for clinical use, block the increased α-synuclein aggregation in G2019S-LRRK2-expressing neurons. These results demonstrate that α-synuclein inclusion formation in neurons can be blocked and that novel therapeutic compounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of PD-associated pathology.

  • Lewy body
  • Lewy neurite
  • LRRK2
  • Parkinson's
  • synuclein
View Full Text
Back to top

In this issue

The Journal of Neuroscience: 36 (28)
Journal of Neuroscience
Vol. 36, Issue 28
13 Jul 2016
  • 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.
G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons
(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
G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons
Laura A. Volpicelli-Daley, Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher, Austen J. Milnerwood, Vivek K. Unni, Warren D. Hirst, Zhenyu Yue, Hien T. Zhao, Kyle Fraser, Richard E. Kennedy, Andrew B. West
Journal of Neuroscience 13 July 2016, 36 (28) 7415-7427; DOI: 10.1523/JNEUROSCI.3642-15.2016

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
G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons
Laura A. Volpicelli-Daley, Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher, Austen J. Milnerwood, Vivek K. Unni, Warren D. Hirst, Zhenyu Yue, Hien T. Zhao, Kyle Fraser, Richard E. Kennedy, Andrew B. West
Journal of Neuroscience 13 July 2016, 36 (28) 7415-7427; DOI: 10.1523/JNEUROSCI.3642-15.2016
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

  • Lewy body
  • Lewy neurite
  • LRRK2
  • Parkinson's
  • synuclein

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

Articles

  • Choice Behavior Guided by Learned, But Not Innate, Taste Aversion Recruits the Orbitofrontal Cortex
  • Maturation of Spontaneous Firing Properties after Hearing Onset in Rat Auditory Nerve Fibers: Spontaneous Rates, Refractoriness, and Interfiber Correlations
  • Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV/AIDS Neurodegeneration
Show more Articles

Neurobiology of Disease

  • Rapid and chronic ethanol tolerance are composed of distinct memory-like states in Drosophila
  • Targeting astrocyte signaling alleviates cerebrovascular and synaptic function deficits in a diet-based mouse model of small cerebral vessel disease
  • TEMPORAL IRREVERSIBILITY OF LARGE-SCALE BRAIN DYNAMICS IN ALZHEIMER'S DISEASE
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 © 2023 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.