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

Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson’s disease

View ORCID ProfileD J Vidyadhara, Mahalakshmi Somayaji, Nigel Wade, Betül Yücel, Helen Zhao, N Shashaank, Joseph Ribaudo, Jyoti Gupta, TuKiet T. Lam, Dalibor Sames, Lois E. Greene, David L. Sulzer, View ORCID ProfileSreeganga S. Chandra
doi: https://doi.org/10.1101/2022.02.04.479203
D J Vidyadhara
1Departments of Neurology
2Neuroscience, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for D J Vidyadhara
Mahalakshmi Somayaji
3Department of Psychiatry, Columbia University, NY, USA
4Division of Molecular Therapeutics, New York State Psychiatric Institute, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nigel Wade
1Departments of Neurology
2Neuroscience, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Betül Yücel
1Departments of Neurology
2Neuroscience, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Helen Zhao
2Neuroscience, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
N Shashaank
5Department of Computer Science, Columbia University, NY, USA
6New York Genome Center, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph Ribaudo
2Neuroscience, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jyoti Gupta
2Neuroscience, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
TuKiet T. Lam
7W. M. Keck Foundation Biotechnology Resource Laboratory, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dalibor Sames
8Department of Chemistry and NeuroTechnology Center, Columbia University, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lois E. Greene
9Laboratory of Cell Biology, NHLBI, National Institutes of Health, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David L. Sulzer
3Department of Psychiatry, Columbia University, NY, USA
4Division of Molecular Therapeutics, New York State Psychiatric Institute, NY, USA
10Departments of Neurology and Pharmacology, Columbia University, NY, USA
11Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sreeganga S. Chandra
1Departments of Neurology
2Neuroscience, Yale University, CT, USA
11Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
12Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sreeganga S. Chandra
  • For correspondence: sreeganga.chandra@yale.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

SUMMARY

Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of- function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin-knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. We demonstrate that auxilin KO mice display the cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Through unbiased proteomic and neurochemical analyses, we demonstrate that dopamine homeostasis is disrupted in auxilin KO brains, including via slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. We also show that elevated macroautophagy and defective SV protein sorting contribute to ineffective dopamine sequestration and homeostasis, ultimately leading to neurodegeneration. This study advances our knowledge of how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.

Competing Interest Statement

The authors have declared no competing interest.

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-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted February 06, 2022.
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.
Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson’s disease
(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
Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson’s disease
D J Vidyadhara, Mahalakshmi Somayaji, Nigel Wade, Betül Yücel, Helen Zhao, N Shashaank, Joseph Ribaudo, Jyoti Gupta, TuKiet T. Lam, Dalibor Sames, Lois E. Greene, David L. Sulzer, Sreeganga S. Chandra
bioRxiv 2022.02.04.479203; doi: https://doi.org/10.1101/2022.02.04.479203
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson’s disease
D J Vidyadhara, Mahalakshmi Somayaji, Nigel Wade, Betül Yücel, Helen Zhao, N Shashaank, Joseph Ribaudo, Jyoti Gupta, TuKiet T. Lam, Dalibor Sames, Lois E. Greene, David L. Sulzer, Sreeganga S. Chandra
bioRxiv 2022.02.04.479203; doi: https://doi.org/10.1101/2022.02.04.479203

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 (3477)
  • Biochemistry (7315)
  • Bioengineering (5290)
  • Bioinformatics (20180)
  • Biophysics (9967)
  • Cancer Biology (7696)
  • Cell Biology (11242)
  • Clinical Trials (138)
  • Developmental Biology (6413)
  • Ecology (9910)
  • Epidemiology (2065)
  • Evolutionary Biology (13266)
  • Genetics (9346)
  • Genomics (12542)
  • Immunology (7665)
  • Microbiology (18919)
  • Molecular Biology (7413)
  • Neuroscience (40853)
  • Paleontology (298)
  • Pathology (1224)
  • Pharmacology and Toxicology (2124)
  • Physiology (3137)
  • Plant Biology (6833)
  • Scientific Communication and Education (1268)
  • Synthetic Biology (1890)
  • Systems Biology (5295)
  • Zoology (1083)