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Sass2009 - Approach to an α-synuclein-based BST model of Parkinson's disease

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  • A pragmatic approach to biochemical systems theory applied to an alpha-synuclein-based model of Parkinson's disease.
  • Sass MB, Lorenz AN, Green RL, Coleman RA
  • Journal of neuroscience methods , 4/ 2009 , Volume 178 , pages: 366-377
  • Department of Chemistry, Integrated Science Center, The College of William and Mary, Williamsburg, VA 23187, USA.
  • This paper presents a detailed systems model of Parkinson's disease (PD), developed utilizing a pragmatic application of biochemical systems theory (BST) intended to assist experimentalists in the study of system behavior. This approach utilizes relative values as a reasonable initial estimate for BST and provides a theoretical means of applying numerical solutions to qualitative and semi-quantitative understandings of cellular pathways and mechanisms. The approach allows for the simulation of human disease through its ability to organize and integrate existing information about metabolic pathways without having a full quantitative description of those pathways, so that hypotheses about individual processes may be tested in a systems environment. Incorporating this method, the PD model describes alpha-synuclein aggregation as mediated by dopamine metabolism, the ubiquitin-proteasome system, and lysosomal degradation, allowing for the examination of dynamic pathway interactions and the evaluation of possible toxic mechanisms in the aggregation process. Four system perturbations: elevated alpha-synuclein aggregation, impaired dopamine packaging, increased neurotoxins, and alpha-synuclein overexpression, were analyzed for correlation to qualitative PD system hypotheses present in the literature, with the model demonstrating a high level of agreement with these hypotheses. Additionally, various PD treatment methods, including levadopa and monoamine oxidase inhibition (MAOI) therapy, were applied to the disease models to examine their effects on the system. Future additions and refinements to the model may further the understanding of the emergent behaviors of the disease, helping in the identification of system sensitivities and possible therapeutic targets.
Audald Lloret i Villas

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  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: Apr 13, 2015 3:55:01 PM
  • Last Modified: Apr 14, 2015 3:38:41 PM
  • Version: 2 public model Download this version
    • Submitted on: Apr 14, 2015 3:38:41 PM
    • Submitted by: Audald Lloret i Villas
    • With comment: Current version of Sass2009 - Approach to an α-synuclein-based BST model of Parkinson's disease
  • Version: 1 public model Download this version
    • Submitted on: Apr 13, 2015 3:55:01 PM
    • Submitted by: Audald Lloret i Villas
    • With comment: Original import of Sass2009 - Approach to an α-synuclein-based BST model of Parkinson's disease
Curator's comment:
(added: 14 Apr 2015, 12:09:56, updated: 14 Apr 2015, 12:09:56)
Figure 15 of the reference publication has been reproduced here. Dynamics of protofibrils, fibrils and Lewy bodies are plotted over 100 time units. This figure displays a percentage comparison of a disease model, where levels of α-synuclein in the system are increased by 10%, and the baseline model. (i.e. α-synuclein increases to 0,22 at disease model). For the sake of simulation, data from both models (disease and baseline) was merged. Subsequently, the disease model was divided by the baseline model and percentage format was applied. The simulation was done using Copasi v4.14 (Build 89) and the plot was generated using Gnuplot. The Copasi file of the baseline model with simulation settings can be downloaded from the below link: