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

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
  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: Sep 10, 2014 10:39:23 AM
  • Last Modified: Oct 30, 2014 1:25:26 PM
Revisions
  • 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.