Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Surface GluA1 and glutamatergic transmission are increased in cortical neurons of a VPS35 D620N knock-in mouse model of parkinsonism and altered by LRRK2 kinase inhibition

Chelsie A Kadgien, Anusha Kamesh, Jaskaran Khinda, Li Ping Cao, Jesse Fox, Matthew J Farrer, View ORCID ProfileAusten J Milnerwood
doi: https://doi.org/10.1101/2021.01.18.427223
Chelsie A Kadgien
1University of British Columbia, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anusha Kamesh
2Montreal Neurological Institute, McGill University, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jaskaran Khinda
1University of British Columbia, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Li Ping Cao
1University of British Columbia, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jesse Fox
1University of British Columbia, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew J Farrer
3University of Florida, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Austen J Milnerwood
2Montreal Neurological Institute, McGill University, 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
  • For correspondence: austen.milnerwood@mcgill.ca
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Vacuolar protein sorting 35 (VPS35) regulates receptor recycling from endosomes. A missense mutation in VPS35 (D620N) leads to autosomal-dominant, late-onset Parkinson’s disease. Here, we use a VPS35 D620N knock-in mouse to study the neurobiology of this mutation. In brain tissue, we confirm previous findings that the mutation results in reduced binding of VPS35 with WASH-complex member FAM21, and robustly elevated phosphorylation of the LRRK2 kinase substrate Rab10. In cultured cortical neurons, the mutation results in increased endosomal recycling protein density (VPS35-FAM21 co-clusters and Rab11 clusters), glutamate release, and GluA1 surface expression. LRRK2 kinase inhibition exerted genotype-specific effects on GluA1 surface expression, but did not impact glutamate release phenotypes. These results improve our understanding of the early effects of the D620N mutation on cellular functions that are specific to neurons. These observations provide candidate pathophysiological pathways that may drive eventual transition to late-stage parkinsonism in VPS35 families, and support a synaptopathy model of neurodegeneration.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted January 19, 2021.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Surface GluA1 and glutamatergic transmission are increased in cortical neurons of a VPS35 D620N knock-in mouse model of parkinsonism and altered by LRRK2 kinase inhibition
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Surface GluA1 and glutamatergic transmission are increased in cortical neurons of a VPS35 D620N knock-in mouse model of parkinsonism and altered by LRRK2 kinase inhibition
Chelsie A Kadgien, Anusha Kamesh, Jaskaran Khinda, Li Ping Cao, Jesse Fox, Matthew J Farrer, Austen J Milnerwood
bioRxiv 2021.01.18.427223; doi: https://doi.org/10.1101/2021.01.18.427223
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Surface GluA1 and glutamatergic transmission are increased in cortical neurons of a VPS35 D620N knock-in mouse model of parkinsonism and altered by LRRK2 kinase inhibition
Chelsie A Kadgien, Anusha Kamesh, Jaskaran Khinda, Li Ping Cao, Jesse Fox, Matthew J Farrer, Austen J Milnerwood
bioRxiv 2021.01.18.427223; doi: https://doi.org/10.1101/2021.01.18.427223

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (4087)
  • Biochemistry (8766)
  • Bioengineering (6480)
  • Bioinformatics (23346)
  • Biophysics (11751)
  • Cancer Biology (9149)
  • Cell Biology (13255)
  • Clinical Trials (138)
  • Developmental Biology (7417)
  • Ecology (11369)
  • Epidemiology (2066)
  • Evolutionary Biology (15088)
  • Genetics (10402)
  • Genomics (14011)
  • Immunology (9122)
  • Microbiology (22050)
  • Molecular Biology (8780)
  • Neuroscience (47373)
  • Paleontology (350)
  • Pathology (1420)
  • Pharmacology and Toxicology (2482)
  • Physiology (3704)
  • Plant Biology (8050)
  • Scientific Communication and Education (1431)
  • Synthetic Biology (2209)
  • Systems Biology (6016)
  • Zoology (1250)