Sass2009 - Approach to an α-synuclein-based BST model of Parkinson's disease
This model is described in the article:
Abstract:
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.
This model is hosted on BioModels Database and identified by: BIOMD0000000575.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.
-
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 , PubMed ID: 19136028
- 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.
Metadata information
Gene Ontology inclusion body assembly
Gene Ontology chaperone-mediated autophagy
Gene Ontology macroautophagy
Gene Ontology dopamine metabolic process
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
|||
| BIOMD0000000575_url.xml | SBML L2V4 representation of Sass2009 - Approach to an α-synuclein-based BST model of Parkinson\s disease | 401.61 KB | Preview | Download |
Additional files |
|||
| BIOMD0000000575.pdf | Auto-generated PDF file | 831.78 KB | Preview | Download |
| Sass2009.cps | Copasi file of the model | 441.57 KB | Preview | Download |
| BIOMD0000000575.vcml | Auto-generated VCML file | 900.00 Bytes | Preview | Download |
| BIOMD0000000575-biopax3.owl | Auto-generated BioPAX (Level 3) | 292.68 KB | Preview | Download |
| BIOMD0000000575.xpp | Auto-generated XPP file | 33.99 KB | Preview | Download |
| BIOMD0000000575.png | Auto-generated Reaction graph (PNG) | 13.11 MB | Preview | Download |
| BIOMD0000000575.sci | Auto-generated Scilab file | 154.00 Bytes | Preview | Download |
| BIOMD0000000575_urn.xml | Auto-generated SBML file with URNs | 394.84 KB | Preview | Download |
| BIOMD0000000575.svg | Auto-generated Reaction graph (SVG) | 561.51 KB | Preview | Download |
| BIOMD0000000575.m | Auto-generated Octave file | 41.32 KB | Preview | Download |
| BIOMD0000000575-biopax2.owl | Auto-generated BioPAX (Level 2) | 209.72 KB | Preview | Download |
- Model originally submitted by : Audald Lloret i Villas
- Submitted: 13-Apr-2015 15:55:01
- Last Modified: 21-Dec-2018 18:13:31
Revisions
-
Version: 3
- Submitted on: 21-Dec-2018 18:13:31
- Submitted by: administrator
- With comment: Include the additional files provided by the submitter in the original submission: Sass2009.cps
-
Version: 2
- Submitted on: 14-Apr-2015 15:38:41
- 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
- Submitted on: 13-Apr-2015 15:55:01
- Submitted by: Audald Lloret i Villas
- With comment: Original import of Sass2009 - Approach to an α-synuclein-based BST model of Parkinson's disease
(*) You might be seeing discontinuous
revisions as only public revisions are displayed here. Any private revisions
of this model will only be shown to the submitter and their collaborators.
: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| E1 Ubiquitin-like modifier-activating enzyme 1 |
0.2 dimensionless |
| Ub E1 Polyubiquitin-B ; Ubiquitin-like modifier-activating enzyme 1 |
0.35 dimensionless |
| UbcH8 Ubiquitin/ISG15-conjugating enzyme E2 L6 |
0.2 dimensionless |
| Fibril Alpha-synuclein ; supramolecular fiber |
0.025 dimensionless |
| Lewy body Alpha-synuclein ; Lewy body |
0.01 dimensionless |
| Dopamine dopamine |
2.0 dimensionless |
| DA quinone dopamine ; quinone |
0.05 dimensionless |
| Reactions | Rate | Parameters |
|---|---|---|
| Ub_E1 + UbcH13_Uev1a => E1 + UbcH13_Uev1a_ub; ATP, Ub_E1, UbcH13_Uev1a, ATP, Ub_E1, UbcH13_Uev1a, ATP, Ub_E1, UbcH13_Uev1a, ATP, Ub_E1, UbcH13_Uev1a, ATP, Ub_E1, UbcH13_Uev1a, ATP, Ub_E1, UbcH13_Uev1a, ATP, Ub_E1, UbcH13_Uev1a, ATP, Ub_E1, UbcH13_Uev1a, ATP, Ub_E1, UbcH13_Uev1a, ATP | Neuronal_cytosol*k29*Ub_E1^g2916*UbcH13_Uev1a^g2971*ATP^g2915 | g2915 = 1.0; g2971 = 1.0; g2916 = 1.0; k29 = 0.05 |
| Ub_E1 + UbcH8 => E1 + UbcH8_Ub; ATP, Ub_E1, UbcH8, ATP, Ub_E1, UbcH8, ATP, Ub_E1, UbcH8, ATP, Ub_E1, UbcH8, ATP, Ub_E1, UbcH8, ATP, Ub_E1, UbcH8, ATP, Ub_E1, UbcH8, ATP, Ub_E1, UbcH8, ATP, Ub_E1, UbcH8, ATP | Neuronal_cytosol*k7*Ub_E1^g716*UbcH8^g717*ATP^g715 | g717 = 1.0; g716 = 1.0; k7 = 0.03; g715 = 1.0 |
| Ub_E1 + UbcH8ub3 => E1 + UbcH8ub4; ATP, Ub_E1, UbcH8ub3, ATP, Ub_E1, UbcH8ub3, ATP, Ub_E1, UbcH8ub3, ATP, Ub_E1, UbcH8ub3, ATP, Ub_E1, UbcH8ub3, ATP, Ub_E1, UbcH8ub3, ATP, Ub_E1, UbcH8ub3, ATP, Ub_E1, UbcH8ub3, ATP, Ub_E1, UbcH8ub3, ATP | Neuronal_cytosol*k28f*Ub_E1^g28f16*UbcH8ub3^g28f69*ATP^g28f15 | k28f = 0.05; g28f16 = 1.0; g28f69 = 1.0; g28f15 = 1.0 |
| UbcH8ub4 => UbcH8 + Ubiquitin; UCH_L1, UbcH8ub4, UCH_L1, UbcH8ub4, UCH_L1, UbcH8ub4, UCH_L1, UbcH8ub4, UCH_L1, UbcH8ub4, UCH_L1, UbcH8ub4, UCH_L1, UbcH8ub4, UCH_L1, UbcH8ub4, UCH_L1, UbcH8ub4, UCH_L1 | Neuronal_cytosol*k28r*UbcH8ub4^g28r70*UCH_L1^g28r30 | k28r = 0.005; g28r30 = 1.0; g28r70 = 1.0 |
| UbcH8ub4 + asyn_UCH_L1 => UCH_L1_asyn_ub4 + UbcH8; UbcH8ub4, asyn_UCH_L1, UbcH8ub4, asyn_UCH_L1, UbcH8ub4, asyn_UCH_L1, UbcH8ub4, asyn_UCH_L1, UbcH8ub4, asyn_UCH_L1, UbcH8ub4, asyn_UCH_L1, UbcH8ub4, asyn_UCH_L1, UbcH8ub4, asyn_UCH_L1, UbcH8ub4, asyn_UCH_L1 | Neuronal_cytosol*k37*UbcH8ub4^g3770*asyn_UCH_L1^g3773 | k37 = 0.05; g3773 = 1.0; g3770 = 1.0 |
| Protofibril => Fibril; Protofibril, Protofibril, Protofibril, Protofibril, Protofibril, Protofibril, Protofibril, Protofibril, Protofibril | Neuronal_cytosol*k2*Protofibril^g22 | k2 = 0.01; g22 = 1.0 |
| Fibril + Parkin_synphilin_1_ub => Lewy_body; Fibril, Parkin_synphilin_1_ub, Fibril, Parkin_synphilin_1_ub, Fibril, Parkin_synphilin_1_ub, Fibril, Parkin_synphilin_1_ub, Fibril, Parkin_synphilin_1_ub, Fibril, Parkin_synphilin_1_ub, Fibril, Parkin_synphilin_1_ub, Fibril, Parkin_synphilin_1_ub, Fibril, Parkin_synphilin_1_ub | Neuronal_cytosol*k3*Fibril^g23*Parkin_synphilin_1_ub^g326 | k3 = 0.007; g23 = 1.0; g326 = 1.0 |
| Protofibril + Protofibril_Ub => Fibril; Protofibril, Protofibril_Ub, Protofibril, Protofibril_Ub, Protofibril, Protofibril_Ub, Protofibril, Protofibril_Ub, Protofibril, Protofibril_Ub, Protofibril, Protofibril_Ub, Protofibril, Protofibril_Ub, Protofibril, Protofibril_Ub, Protofibril, Protofibril_Ub | Neuronal_cytosol*k35*Protofibril^g352*Protofibril_Ub^g3576 | g352 = 1.0; k35 = 0.001; g3576 = 1.0 |
| Fibril + Hsc70 => Hsc70_fibril; Fibril, Hsc70, Fibril, Hsc70, Fibril, Hsc70, Fibril, Hsc70, Fibril, Hsc70, Fibril, Hsc70, Fibril, Hsc70, Fibril, Hsc70, Fibril, Hsc70 | Neuronal_cytosol*k45*Fibril^g453*Hsc70^g4584 | g4584 = 1.0; k45 = 0.04; g453 = 1.0 |
| Fibril + Preautophagosome_membrane => Autophagosome_0; Fibril, Preautophagosome_membrane, Fibril, Preautophagosome_membrane, Fibril, Preautophagosome_membrane, Fibril, Preautophagosome_membrane, Fibril, Preautophagosome_membrane, Fibril, Preautophagosome_membrane, Fibril, Preautophagosome_membrane, Fibril, Preautophagosome_membrane, Fibril, Preautophagosome_membrane | k52*Fibril^g523*Preautophagosome_membrane^g5280 | g5280 = 1.0; g523 = 1.0; k52 = 0.05 |
| Lewy_body + Preautophagosome_membrane => Autophagosome_0; Lewy_body, Preautophagosome_membrane, Lewy_body, Preautophagosome_membrane, Lewy_body, Preautophagosome_membrane, Lewy_body, Preautophagosome_membrane, Lewy_body, Preautophagosome_membrane, Lewy_body, Preautophagosome_membrane, Lewy_body, Preautophagosome_membrane, Lewy_body, Preautophagosome_membrane, Lewy_body, Preautophagosome_membrane | k53*Lewy_body^g534*Preautophagosome_membrane^g5380 | g5380 = 1.0; g534 = 1.0; k53 = 0.05 |
| L_Dopa => Dopamine + CO2; DDC, L_Dopa, DDC, L_Dopa, DDC, L_Dopa, DDC, L_Dopa, DDC, L_Dopa, DDC, L_Dopa, DDC, L_Dopa, DDC, L_Dopa, DDC, L_Dopa, DDC | Neuronal_cytosol*k14*L_Dopa^g1437*DDC^g1467 | k14 = 3.0; g1467 = 1.0; g1437 = 1.0 |
| Dopamine + O2_0 => DA_quinone + O2; Dopamine, O2_0, Dopamine, O2_0, Dopamine, O2_0, Dopamine, O2_0, Dopamine, O2_0, Dopamine, O2_0, Dopamine, O2_0, Dopamine, O2_0, Dopamine, O2_0 | Neuronal_cytosol*k18*Dopamine^g186*O2_0^g1851 | k18 = 0.02; g186 = 1.0; g1851 = 1.0 |
(added: 14 Apr 2015, 12:09:56, updated: 14 Apr 2015, 12:09:56)