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

A double-hit in vivo model of GBA1 viral microRNA-mediated downregulation and human alpha-synuclein overexpression demonstrates nigrostriatal degeneration

Alexia Polissidis, Georgia Nikolopoulou, Effrosyni Koronaiou, Maria Nikatou, Catherine Viel, Marios Boyongo, S. Pablo Sardi, Maria Xilouri, Kostas Vekrellis, Leonidas Stefanis
doi: https://doi.org/10.1101/2021.06.23.449545
Alexia Polissidis
aCenter of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou St, 11527, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: apolissidis@bioacademy.gr lstefanis@bioacademy.gr
Georgia Nikolopoulou
bCenter of Basic Research, BRFAA, 4 Soranou Efesiou St, 11527, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Effrosyni Koronaiou
aCenter of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou St, 11527, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria Nikatou
aCenter of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou St, 11527, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Catherine Viel
cRare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marios Boyongo
aCenter of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou St, 11527, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Pablo Sardi
cRare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria Xilouri
aCenter of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou St, 11527, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kostas Vekrellis
bCenter of Basic Research, BRFAA, 4 Soranou Efesiou St, 11527, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Leonidas Stefanis
aCenter of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou St, 11527, Athens, Greece
dst, 11527, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: apolissidis@bioacademy.gr lstefanis@bioacademy.gr
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Preclinical and clinical studies support a strong association between mutations in the GBA1 gene that encodes β-glucocerebrosidase (GCase) (EC 3.2.1.45; glucosylceramidase beta) and Parkinson’s disease (PD). Alpha-synuclein (AS), a key player in PD pathogenesis, and GBA1 mutations may independently and synergistically cause lysosomal dysfunction and thus, embody clinically well-validated targets of the neurodegenerative disease process in PD. However, double-hit in vivo models, recapitulating pathological features of PD that can be used to dissect the nature of the complex relationship between GCase and AS on the nigrostriatal axis, the region particularly vulnerable in PD, are direly needed. To address this, we implemented a bidirectional approach in mice to examine the effects of: 1) GCase overexpression (wildtype and mutant N370S) on endogenous AS levels and 2) downregulation of endogenous GCase combined with AS overexpression. Striatal delivery of viral-mediated GCase overexpression revealed minimal effects on cortical and nigrostriatal AS tissue levels and no significant effect on dopaminergic system integrity. On the other hand, microRNA (miR)-mediated GBA1 downregulation (miR GBA), combined with virus-mediated human AS overexpression (+AS), yields decreased GCase activity in the cortex, mimicking levels seen in GBA1 heterozygous carriers (30-40%), increased astrogliosis and microgliosis, decreased striatal dopamine levels (50% compared to controls) and loss of nigral dopaminergic neurons (~33%)-effects that were all reversible with miR rescue. Most importantly, the synergistic neurodegeneration of miR GBA+AS correlated with augmented AS accumulation and extracellular release in the striatum. Collectively, our results suggest that GCase downregulation alone is not sufficient to recapitulate key pathological features of PD in vivo, but its synergistic interplay with AS, via increased AS levels and release, drives nigrostriatal neurodegeneration. Furthermore, we demonstrate a novel double-hit model that can be used to identify putative mechanisms driving PD pathophysiology and can be subsequently used to test novel therapeutic approaches.

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 June 23, 2021.
Download PDF

Supplementary Material

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.
A double-hit in vivo model of GBA1 viral microRNA-mediated downregulation and human alpha-synuclein overexpression demonstrates nigrostriatal degeneration
(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
A double-hit in vivo model of GBA1 viral microRNA-mediated downregulation and human alpha-synuclein overexpression demonstrates nigrostriatal degeneration
Alexia Polissidis, Georgia Nikolopoulou, Effrosyni Koronaiou, Maria Nikatou, Catherine Viel, Marios Boyongo, S. Pablo Sardi, Maria Xilouri, Kostas Vekrellis, Leonidas Stefanis
bioRxiv 2021.06.23.449545; doi: https://doi.org/10.1101/2021.06.23.449545
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
A double-hit in vivo model of GBA1 viral microRNA-mediated downregulation and human alpha-synuclein overexpression demonstrates nigrostriatal degeneration
Alexia Polissidis, Georgia Nikolopoulou, Effrosyni Koronaiou, Maria Nikatou, Catherine Viel, Marios Boyongo, S. Pablo Sardi, Maria Xilouri, Kostas Vekrellis, Leonidas Stefanis
bioRxiv 2021.06.23.449545; doi: https://doi.org/10.1101/2021.06.23.449545

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 (9150)
  • Cell Biology (13255)
  • Clinical Trials (138)
  • Developmental Biology (7417)
  • Ecology (11370)
  • Epidemiology (2066)
  • Evolutionary Biology (15088)
  • Genetics (10402)
  • Genomics (14012)
  • Immunology (9122)
  • Microbiology (22050)
  • Molecular Biology (8780)
  • Neuroscience (47375)
  • 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)