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

The proSAAS chaperone provides neuroprotection and attenuates transsynaptic α–synuclein spread in rodent models of Parkinson’s disease

View ORCID ProfileIris Lindberg, Zhan Shu, Hoa Lam, Michael Helwig, Nur Yucer, Alexander Laperle, Clive Svendsen, Donato A. Di Monte, Nigel T. Maidment
doi: https://doi.org/10.1101/2021.09.29.462435
Iris Lindberg
1University of Maryland-Baltimore
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Iris Lindberg
  • For correspondence: ilindberg@som.umaryland.edu nmaidmen@ucla.edu
Zhan Shu
2University of California-Los Angeles
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hoa Lam
2University of California-Los Angeles
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Helwig
3German Center for Neurodegenerative Disease (DZNE)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nur Yucer
4Cedars-Sinai Medical Center, Los Angeles
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexander Laperle
4Cedars-Sinai Medical Center, Los Angeles
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clive Svendsen
4Cedars-Sinai Medical Center, Los Angeles
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donato A. Di Monte
3German Center for Neurodegenerative Disease (DZNE)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nigel T. Maidment
2University of California-Los Angeles
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ilindberg@som.umaryland.edu nmaidmen@ucla.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

Parkinson’s disease is a devastating motor disorder involving the aberrant aggregation of the synaptic protein synuclein (aSyn) and degeneration of the nigrostriatal dopaminergic tract. We previously showed that proSAAS, a small secreted chaperone protein widely expressed in neurons within the brain, is able to block aSyn-induced dopaminergic cytotoxicity in primary nigral neuron cultures. We show here that coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This positive functional outcome was accompanied by significant amelioration of the human aSyn-induced loss of both nigral tyrosine hydroxylase-positive cells and striatal tyrosine hydroxylase-positive terminals, demonstrating clear proSAAS-mediated protection of the nigro-striatal tract. ProSAAS overexpression also reduced the content of human aSyn protein in both the nigra and striatum and reduced the loss of tyrosine hydroxylase protein in both regions. Since proSAAS is a secreted protein, we tested the possibility that proSAAS is able to block the transsynaptic spread of aSyn from the periphery to the central nervous system, increasingly recognized as a potentially significant pathological mechanism. The number of human aSyn-positive neurites in the pons and caudal midbrain of mice following administration of human aSyn-encoding AAV into the vagus nerve was considerably reduced in mice coinjected with proSAAS-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. We suggest that proSAAS may represent a promising target for therapeutic development in Parkinson’s disease.

Significance This paper describes two independent avenues of research that both provide support for the in vivo neuroprotective function of this small chaperone protein. In the first approach, we show that proSAAS overexpression provides remarkably effective protection against dopaminergic neurotoxicity in a rat model of Parkinson’s disease. This conclusion is supported both by three independent assays of motor function as well as by quantitative analysis of surviving dopaminergic neurons in brain areas involved in the control of motor function. In the second line of research, we show that in mice, the spread of human synuclein across synapses can be blunted by proSAAS overexpression.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    AAV
    adeno-associated virus
    aSyn
    alpha synuclein
    cMB
    caudal midbrain
    DA
    dopamine
    DMV
    dorsal motor nucleus of the vagus
    GFP
    green fluorescent protein
    MO
    medulla oblongata
    NTS
    nucleus tractus solitarius
    rMB
    rostral midbrain
    SNc
    substantia nigra pars compacta
    TH
    tyrosine hydroxylase
  • 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 October 01, 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.
    The proSAAS chaperone provides neuroprotection and attenuates transsynaptic α–synuclein spread in rodent models of 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
    The proSAAS chaperone provides neuroprotection and attenuates transsynaptic α–synuclein spread in rodent models of Parkinson’s disease
    Iris Lindberg, Zhan Shu, Hoa Lam, Michael Helwig, Nur Yucer, Alexander Laperle, Clive Svendsen, Donato A. Di Monte, Nigel T. Maidment
    bioRxiv 2021.09.29.462435; doi: https://doi.org/10.1101/2021.09.29.462435
    Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
    Citation Tools
    The proSAAS chaperone provides neuroprotection and attenuates transsynaptic α–synuclein spread in rodent models of Parkinson’s disease
    Iris Lindberg, Zhan Shu, Hoa Lam, Michael Helwig, Nur Yucer, Alexander Laperle, Clive Svendsen, Donato A. Di Monte, Nigel T. Maidment
    bioRxiv 2021.09.29.462435; doi: https://doi.org/10.1101/2021.09.29.462435

    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 (4235)
    • Biochemistry (9136)
    • Bioengineering (6784)
    • Bioinformatics (24001)
    • Biophysics (12129)
    • Cancer Biology (9534)
    • Cell Biology (13778)
    • Clinical Trials (138)
    • Developmental Biology (7636)
    • Ecology (11702)
    • Epidemiology (2066)
    • Evolutionary Biology (15513)
    • Genetics (10644)
    • Genomics (14326)
    • Immunology (9483)
    • Microbiology (22840)
    • Molecular Biology (9090)
    • Neuroscience (48995)
    • Paleontology (355)
    • Pathology (1482)
    • Pharmacology and Toxicology (2570)
    • Physiology (3846)
    • Plant Biology (8331)
    • Scientific Communication and Education (1471)
    • Synthetic Biology (2296)
    • Systems Biology (6192)
    • Zoology (1301)