Sneppen2009 - Modeling proteasome dynamics in Parkinson's disease

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Sneppen2009 - Modeling proteasome dynamics in Parkinson's disease

This model is described in the article:

Sneppen K, Lizana L, Jensen MH, Pigolotti S, Otzen D.
Phys Biol 2009; 6(3): 036005

Abstract:

In Parkinson's disease (PD), there is evidence that alpha-synuclein (alphaSN) aggregation is coupled to dysfunctional or overburdened protein quality control systems, in particular the ubiquitin-proteasome system. Here, we develop a simple dynamical model for the on-going conflict between alphaSN aggregation and the maintenance of a functional proteasome in the healthy cell, based on the premise that proteasomal activity can be titrated out by mature alphaSN fibrils and their protofilament precursors. In the presence of excess proteasomes the cell easily maintains homeostasis. However, when the ratio between the available proteasome and the alphaSN protofilaments is reduced below a threshold level, we predict a collapse of homeostasis and onset of oscillations in the proteasome concentration. Depleted proteasome opens for accumulation of oligomers. Our analysis suggests that the onset of PD is associated with a proteasome population that becomes occupied in periodic degradation of aggregates. This behavior is found to be the general state of a proteasome/chaperone system under pressure, and suggests new interpretations of other diseases where protein aggregation could stress elements of the protein quality control system.

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Format
SBML (L2V4)
Related Publication
  • Modeling proteasome dynamics in Parkinson's disease.
  • Sneppen K, Lizana L, Jensen MH, Pigolotti S, Otzen D
  • Physical biology , 0/ 2009 , Volume 6 , pages: 036005
  • Niels Bohr Institute, Copenhagen, Denmark. sneppen@nbi.dk
  • In Parkinson's disease (PD), there is evidence that alpha-synuclein (alphaSN) aggregation is coupled to dysfunctional or overburdened protein quality control systems, in particular the ubiquitin-proteasome system. Here, we develop a simple dynamical model for the on-going conflict between alphaSN aggregation and the maintenance of a functional proteasome in the healthy cell, based on the premise that proteasomal activity can be titrated out by mature alphaSN fibrils and their protofilament precursors. In the presence of excess proteasomes the cell easily maintains homeostasis. However, when the ratio between the available proteasome and the alphaSN protofilaments is reduced below a threshold level, we predict a collapse of homeostasis and onset of oscillations in the proteasome concentration. Depleted proteasome opens for accumulation of oligomers. Our analysis suggests that the onset of PD is associated with a proteasome population that becomes occupied in periodic degradation of aggregates. This behavior is found to be the general state of a proteasome/chaperone system under pressure, and suggests new interpretations of other diseases where protein aggregation could stress elements of the protein quality control system.
Contributors
Audald Lloret i Villas, administrator

Metadata information

is
BioModels Database MODEL1409100000
BioModels Database BIOMD0000000548
isDescribedBy
PubMed 19411740
hasTaxon
Taxonomy Homo sapiens
hasProperty
Human Disease Ontology Parkinson's disease
Curation status
Curated
Name Description Size Actions

Model files

BIOMD0000000548_url.xml SBML L2V4 representation of Sneppen2009 - Modeling proteasome dynamics in Parkinson\s disease 16.17 KB Preview | Download

Additional files

BIOMD0000000548_urn.xml Auto-generated SBML file with URNs 15.96 KB Preview | Download
BIOMD0000000548.xpp Auto-generated XPP file 1.21 KB Preview | Download
BIOMD0000000548.vcml Auto-generated VCML file 900.00 bytes Preview | Download
BIOMD0000000548-biopax3.owl Auto-generated BioPAX (Level 3) 5.90 KB Preview | Download
BIOMD0000000548.png Auto-generated Reaction graph (PNG) 5.04 KB Preview | Download
BIOMD0000000548.pdf Auto-generated PDF file 124.85 KB Preview | Download
BIOMD0000000548.svg Auto-generated Reaction graph (SVG) 851.00 bytes Preview | Download
BIOMD0000000548.sci Auto-generated Scilab file 154.00 bytes Preview | Download
Sneppen2009.cps Copasi file of the model 30.92 KB Preview | Download
BIOMD0000000548-biopax2.owl Auto-generated BioPAX (Level 2) 5.53 KB Preview | Download
BIOMD0000000548.m Auto-generated Octave file 3.01 KB Preview | Download

  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: Sep 10, 2014 10:39:23 AM
  • Last Modified: Dec 21, 2018 5:34:28 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 5:34:28 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: Sneppen2009.cps
  • Version: 2 public model Download this version
    • Submitted on: Oct 30, 2014 1:25:26 PM
    • Submitted by: Audald Lloret i Villas
    • With comment: Current version of Sneppen2009 - Modeling proteasome dynamics in Parkinson's disease
  • Version: 1 public model Download this version
    • Submitted on: Sep 10, 2014 10:39:23 AM
    • Submitted by: Audald Lloret i Villas
    • With comment: Original import of Sneppen2009 - Modeling proteasome dynamics in Parkinson's disease
Curator's comment:
(added: 10 Sep 2014, 12:15:50, updated: 10 Sep 2014, 12:15:50)
Figure 3 of the reference publication has been reproduced here. Dynamics of proteasome (P), fibrils (F) and the complex (C) concentration are plotted during 150 arbitrary units. The simulation was done using Copasi v4.12 (Build 81) and the plots were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link.