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

Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?

View ORCID ProfileIvan A. Kuznetsov, View ORCID ProfileAndrey V. Kuznetsov
doi: https://doi.org/10.1101/2021.05.09.443304
Ivan A. Kuznetsov
aPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
bDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ivan A. Kuznetsov
Andrey V. Kuznetsov
cDepartment of Mechanical and Aerospace Engineering, North Carolina State University, Raleigh, NC 27695-7910, USA; e-mail:
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andrey V. Kuznetsov
  • For correspondence: avkuznet@ncsu.edu avkuznet@ncsu.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Finding the causative pathophysiological mechanisms for Parkinson’s disease (PD) is important for developing therapeutic interventions. Until recently, it was believed that Lewy bodies (LBs), the hallmark of PD, are mostly composed of alpha-synuclein (α-syn) fibrils. Recent results (Shahmoradian et al., Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes, Nature Neuroscience 22 (2019) 1099-1109) demonstrated that the fibrillar form of α-syn is lacking from LBs. Here we propose that this surprising observation can be explained by the catalytic activity of the fibrillar form of α-syn. We assumed that α-syn fibrils catalyze the formation of LBs, but do not become part of them. We developed a mathematical model based on this hypothesis. By using the developed model, we investigated the consequences of this hypothesis. In particular, the model suggests that the long incubation time of PD can be explained by a two-step aggregation process that leads to its development: (i) aggregation of monomeric α-syn into α-syn oligomers and fibrils and (ii) clustering of membrane-bound organelles, which may cause disruption of axonal trafficking and lead to neuron starvation and death. The model shows that decreasing the rate of destruction of α-syn aggregates in somatic lysosomes accelerates the formation of LBs. Another consequence of the model is the prediction that removing α-syn aggregates from the brain after the aggregation of membrane-bound organelles into LBs has started may not stop the progression of PD because LB formation is an autocatalytic process; hence, the formation of LBs will be catalyzed by aggregates of membrane-bound organelles even in the absence of α-syn aggregates. The performed sensitivity study made it possible to establish the hierarchy of model parameters with respect to their effect on the formation of vesicle aggregates in the soma.

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 May 09, 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.
Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?
(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
Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?
Ivan A. Kuznetsov, Andrey V. Kuznetsov
bioRxiv 2021.05.09.443304; doi: https://doi.org/10.1101/2021.05.09.443304
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?
Ivan A. Kuznetsov, Andrey V. Kuznetsov
bioRxiv 2021.05.09.443304; doi: https://doi.org/10.1101/2021.05.09.443304

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

  • Biophysics
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)