Sass2009 - Approach to an α-synuclein-based BST model of Parkinson's disease
Model Identifier
BIOMD0000000575
Short description
Sass2009 - Approach to an
α-synuclein-based BST model of Parkinson's disease
This model is described in the article:
J. Neurosci. Methods 2009 Apr; 178(2):
366-377
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.
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Format
SBML
(L2V4)
Related Publication
-
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.
Contributors
Audald Lloret i Villas, administrator
Metadata information
is
isDescribedBy
hasTaxon
isVersionOf
Gene Ontology
proteasome-mediated ubiquitin-dependent protein catabolic process
Gene Ontology inclusion body assembly
Gene Ontology chaperone-mediated autophagy
Gene Ontology macroautophagy
Gene Ontology dopamine metabolic process
Gene Ontology inclusion body assembly
Gene Ontology chaperone-mediated autophagy
Gene Ontology macroautophagy
Gene Ontology dopamine metabolic process
hasProperty
Curation status
Curated
Tags
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| 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 |
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| Sass2009.cps | Copasi file of the model | 441.57 KB | Preview | Download |
| BIOMD0000000575.m | Auto-generated Octave file | 41.32 KB | Preview | Download |
| BIOMD0000000575.svg | Auto-generated Reaction graph (SVG) | 561.51 KB | Preview | Download |
| BIOMD0000000575-biopax3.owl | Auto-generated BioPAX (Level 3) | 292.68 KB | 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.xpp | Auto-generated XPP file | 33.99 KB | Preview | Download |
| BIOMD0000000575.vcml | Auto-generated VCML file | 900.00 bytes | Preview | Download |
| BIOMD0000000575-biopax2.owl | Auto-generated BioPAX (Level 2) | 209.72 KB | Preview | Download |
| BIOMD0000000575.pdf | Auto-generated PDF file | 831.78 KB | Preview | Download |
| BIOMD0000000575.png | Auto-generated Reaction graph (PNG) | 13.11 MB | 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
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| Lewy body Alpha-synuclein ; Lewy body |
0.01 dimensionless |
| Dopamine dopamine |
2.0 dimensionless |
| Neuromelanin 5,6-dihydroxyindole ; polymer |
1.0 dimensionless |
| Alpha synuclein Alpha-synuclein |
0.2 dimensionless |
| Neurotoxins neurotoxin |
0.01 dimensionless |
| Bioamines amine ; biological role |
0.1 dimensionless |
| O2 dioxygen |
2.0 dimensionless |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| (Lewy_body + Preautophagosome_membrane) => (Autophagosome) ([Alpha-synuclein; Lewy body] + [autophagosome membrane]) => ([autophagosome]) |
k53*Lewy_body^g534*Preautophagosome_membrane^g5380 k53*[Alpha-synuclein; Lewy body]^g534*[autophagosome membrane]^g5380 |
g5380 = 1.0; g534 = 1.0; k53 = 0.05 |
| (L-Dopa) => (Dopamine + CO2) ([L-dopa]) => ([dopamine] + [carbon dioxide]) |
Neuronal_cytosol*k14*L_Dopa^g1437*DDC^g1467 Neuronal_cytosol*k14*[L-dopa]^g1437*[Aromatic-L-amino-acid decarboxylase]^g1467 |
k14 = 3.0; g1467 = 1.0; g1437 = 1.0 |
| (Dopamine + Vesicle) => (V-DA) ([dopamine] + [vesicle]) => ([dopamine]) |
k15*Dopamine^g156*Vesicle_0^g1544*VMAT2^g1545 k15*[dopamine]^g156*[vesicle]^g1544*[Synaptic vesicular amine transporter]^g1545 |
g156 = 1.0; k15 = 0.2; g1545 = 1.0; g1544 = 1.0 |
| (L-Dopa + O2 + Cysteine) => (Neuromelanin + H2O2 + CO2) ([L-dopa] + [dioxygen] + [cysteine]) => ([5,6-dihydroxyindole; polymer] + [hydrogen peroxide] + [carbon dioxide]) |
Neuronal_cytosol*k100*L_Dopa^g10037*O2_0^g10051*Cysteine^g100115 Neuronal_cytosol*k100*[L-dopa]^g10037*[dioxygen]^g10051*[cysteine]^g100115 |
g10051 = 1.0; g100115 = 1.0; g10037 = 1.0; k100 = 0.005 |
| (L-Tyr + O2 + Cysteine) => (Neuromelanin + H2O2 + CO2) ([L-tyrosine] + [dioxygen] + [cysteine]) => ([5,6-dihydroxyindole; polymer] + [hydrogen peroxide] + [carbon dioxide]) |
Neuronal_cytosol*k101*L_Tyr^g10136*O2_0^g10151*Cysteine^g101115 Neuronal_cytosol*k101*[L-tyrosine]^g10136*[dioxygen]^g10151*[cysteine]^g101115 |
k101 = 0.005; g101115 = 1.0; g10151 = 1.0; g10136 = 1.0 |
| (DA_quinone + O2 + Cysteine) => (Neuromelanin + CO2) ([dopamine; quinone] + [dioxygen] + [cysteine]) => ([5,6-dihydroxyindole; polymer] + [carbon dioxide]) |
Neuronal_cytosol*k102*DA_quinone^g10210*O2_0^g10251*Cysteine^g102115 Neuronal_cytosol*k102*[dopamine; quinone]^g10210*[dioxygen]^g10251*[cysteine]^g102115 |
g10251 = 1.0; g10210 = 1.0; k102 = 0.005; g102115 = 1.0 |
| (Fe3+ + Neuromelanin) => (Neuromelanin-ntox-Fe3+) ([iron(3+)] + [5,6-dihydroxyindole; polymer]) => ([polymer; 5,6-dihydroxyindole; iron(3+); neurotoxin]) |
Neuronal_cytosol*k115*Fe3^g11565*Neuromelanin^g115118 Neuronal_cytosol*k115*[iron(3+)]^g11565*[5,6-dihydroxyindole; polymer]^g115118 |
g115118 = 1.0; g11565 = 1.0; k115 = 0.5 |
| (Alpha_synuclein + Hsc70) => (Hsc70-asyn) ([Alpha-synuclein] + [Heat shock cognate 71 kDa protein]) => ([Alpha-synuclein; Heat shock cognate 71 kDa protein]) |
Neuronal_cytosol*k43*Alpha_synuclein^g431*Hsc70^g4384 Neuronal_cytosol*k43*[Alpha-synuclein]^g431*[Heat shock cognate 71 kDa protein]^g4384 |
k43 = 0.05; g431 = 1.0; g4384 = 1.0 |
| (Alpha_synuclein + Preautophagosome_membrane) => (Autophagosome) ([Alpha-synuclein] + [autophagosome membrane]) => ([autophagosome]) |
k50*Alpha_synuclein^g501*Preautophagosome_membrane^g5080 k50*[Alpha-synuclein]^g501*[autophagosome membrane]^g5080 |
g501 = 1.0; g5080 = 1.0; k50 = 0.05 |
| (Neuromelanin + Neurotoxins) => (Neuromelanin-ntox-Fe3+) ([5,6-dihydroxyindole; polymer] + [neurotoxin]) => ([polymer; 5,6-dihydroxyindole; iron(3+); neurotoxin]) |
Neuronal_cytosol*k116*Neuromelanin^g116118*Neurotoxins^g11642 Neuronal_cytosol*k116*[5,6-dihydroxyindole; polymer]^g116118*[neurotoxin]^g11642 |
k116 = 0.5; g11642 = 1.0; g116118 = 1.0 |
| (Bioamines + Vesicle) => (V-ntox-ba) ([amine; biological role] + [vesicle]) => ([neurotoxin; amine; biological role]) |
k16*Bioamines^g1643*Vesicle_0^g1644 k16*[amine; biological role]^g1643*[vesicle]^g1644 |
k16 = 1.0E-4; g1644 = 1.0; g1643 = 1.0 |
| (Dopamine + O2) => (DA_quinone + O2-) ([dopamine] + [dioxygen]) => ([dopamine; quinone] + [superoxide]) |
Neuronal_cytosol*k18*Dopamine^g186*O2_0^g1851 Neuronal_cytosol*k18*[dopamine]^g186*[dioxygen]^g1851 |
k18 = 0.02; g186 = 1.0; g1851 = 1.0 |
| (Dopamine + O2 + H2O) => (NH3 + DOPAL + H2O2) ([dopamine] + [dioxygen] + [water]) => ([ammonia] + [3,4-dihydroxyphenylacetaldehyde] + [hydrogen peroxide]) |
Neuronal_cytosol*k19*Dopamine^g196*O2_0^g1951*H2O^g1960*MAO^g1953 Neuronal_cytosol*k19*[dopamine]^g196*[dioxygen]^g1951*[water]^g1960*[Amine oxidase [flavin-containing] A]^g1953 |
g1960 = 1.0; g196 = 1.0; k19 = 0.01; g1953 = 1.0; g1951 = 1.0 |
| (H2O2) => (H2O + O2) ([hydrogen peroxide]) => ([water] + [dioxygen]) |
Neuronal_cytosol*k22*H2O2^g229*Catalase^g2259 Neuronal_cytosol*k22*[hydrogen peroxide]^g229*[Catalase]^g2259 |
g2259 = 1.0; g229 = 1.0; k22 = 0.5 |
| (O2-) => (H2O2 + O2) ([superoxide]) => ([hydrogen peroxide] + [dioxygen]) |
Neuronal_cytosol*k56*O2^g5686*SOD^g5687 Neuronal_cytosol*k56*[superoxide]^g5686*[Superoxide dismutase [Cu-Zn]]^g5687 |
g5687 = 1.0; g5686 = 1.0; k56 = 0.05 |
Curator's comment:
(added: 14 Apr 2015, 12:09:56, updated: 14 Apr 2015, 12:09:56)
(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: