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BIOMD0000000559 - Ouzounoglou2014 - Modeling of alpha-synuclein effects on neuronal homeostasis

 

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Reference Publication
Publication ID: 24885905
Ouzounoglou E, Kalamatianos D, Emmanouilidou E, Xilouri M, Stefanis L, Vekrellis K, Manolakos ES.
In silico modeling of the effects of alpha-synuclein oligomerization on dopaminergic neuronal homeostasis.
BMC Syst Biol 2014; 8: 54
  [more]
Model
Original Model: BIOMD0000000559.origin
Submitter: Eleftherios Ouzounoglou
Submission ID: MODEL1412010000
Submission Date: 01 Dec 2014 22:06:53 UTC
Last Modification Date: 08 Apr 2016 18:44:36 UTC
Creation Date: 20 Nov 2014 17:56:57 UTC
Encoders:  Audald Lloret i Villas
   Eleftherios Ouzounoglou
set #1
bqbiol:hasProperty Human Disease Ontology DOID:14330
bqbiol:isVersionOf Gene Ontology inclusion body assembly
Gene Ontology regulation of dopamine metabolic process
Gene Ontology protein catabolic process
Gene Ontology autophagy
bqbiol:hasTaxon Taxonomy Homo sapiens
Notes
Ouzounoglou2014 - Modeling of alpha-synuclein effects on neuronal homeostasis

This model is described in the article:

Ouzounoglou E, Kalamatianos D, Emmanouilidou E, Xilouri M, Stefanis L, Vekrellis K, Manolakos ES.
BMC Syst Biol 2014; 8: 54

Abstract:

BACKGROUND: Alpha-synuclein (ASYN) is central in Parkinson's disease (PD) pathogenesis. Converging pieces of evidence suggest that the levels of ASYN expression play a critical role in both familial and sporadic Parkinson's disease. ASYN fibrils are the main component of inclusions called Lewy Bodies (LBs) which are found mainly in the surviving neurons of the substantia nigra. Despite the accumulated knowledge regarding the involvement of ASYN in molecular mechanisms underlying the development of PD, there is much information missing which prevents understanding the causes of the disease and how to stop its progression. RESULTS: Using a Systems Biology approach, we develop a biomolecular reactions model that describes the intracellular ASYN dynamics in relation to overexpression, post-translational modification, oligomerization and degradation of the protein. Especially for the proteolysis of ASYN, the model takes into account the biological knowledge regarding the contribution of Chaperone Mediated Autophagy (CMA), macro-autophagic and proteasome pathways in the protein's degradation. Importantly, inhibitory phenomena, caused by ASYN, concerning CMA (more specifically the lysosomal-associated membrane protein 2a, abbreviated as Lamp2a receptor, which is the rate limiting step of CMA) and the proteasome are carefully modeled. The model is validated by simulation studies of known experimental overexpression data from SH-SY5Y cells and the unknown model parameters are estimated either computationally or by experimental fitting. The calibrated model is then tested under three hypothetical intervention scenarios and in all cases predicts increased cell viability that agrees with experimental evidence. The biomodel has been annotated and is made available in SBML format. CONCLUSIONS: The mathematical model presented here successfully simulates the dynamic phenomena of ASYN overexpression and oligomerization and predicts the biological system's behavior in a number of scenarios not used for model calibration. It allows, for the first time, to qualitatively estimate the protein levels that are capable of deregulating proteolytic homeostasis. In addition, it can help form new hypotheses for intervention that could be tested experimentally.


Note: The model contains reactions of species located in different compartments. If the model is applied using volume sizes unequal to one, an extension of the model might be reasonable to guarantee mass conservation.


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.

Model
Publication ID: 24885905 Submission Date: 01 Dec 2014 22:06:53 UTC Last Modification Date: 08 Apr 2016 18:44:36 UTC Creation Date: 20 Nov 2014 17:56:57 UTC
Mathematical expressions
Reactions
WTasynSynthesis DopProduction 2merForm WTasynDopModification
WTasynLampBind AutophagosomeUptakeWTasyn2mer 3merForm WTasyn2LampBind
AutophagosomeUptakeWTasyn3mer 4merForm 3merProtBind AutophagosomeUptakeWTasyn4mer
5merForm 4merProtBind AutophagosomeUptakeWTasyn5mer 6merForm
5merProtBind WTasyn5merBindOnLamp AutophagosomeUptakeWTasyn6mer 7merForm
6merProtBind AutophagosomeUptakeWTasyn7mer 8merForm 7merProtBind
WTasyn7merBindOnLamp AutophagosomeUptakeWTasyn8mer 9merForm 8merProtBind
9merProtBind WTasyn9merBindOnLamp DopamineDegr DopMod2merForm
DopWTasyn2merFormOnLamp DopWTasyn7merFormOnLamp DopWTasyn8merFormOnLamp DopWTasyn9merFormOnLamp
WTasynLysosUptake WTasyn2LysosUptake M/autophagyWTasyn4Degr M/autophagyWTasyn8Degr
M/autophagyWTasyn3Degr M/autophagyWTasyn2Degr M/autophagyWTasyn7Degr M/autophagyWTasyn5Degr
M/autophagyWTasyn6Degr AggregForm DopModAutophagosomeUptake2mer DopMod3merForm
DopModAutophagosomeUptake3mer DopMod4merForm DopMod3merProtBind DopModAutophagosomeUptake4mer
DopMod5merForm DopMod4merProtBind DopModAutophagosomeUptake5mer DopMod6merForm
DopMod5merProtBind DopModAutophagosomeUptake6mer DopMod7merForm DopMod6merProtBind
DopModAutophagosomeUptake7mer DopMod8merForm DopMod7merProtBind DopModAutophagosomeUptake8mer
DopMod9merForm DopMod8merProtBind DopMod9merProtBind WTasyn2merCMADegr
WTasyn1merCMADegr LampFree9merWT DopWTasyn3merFormOnLamp DopWTasyn4merFormOnLamp
DopWTasyn5merFormOnLamp DopWTasyn6merFormOnLamp LampFree3merWT LampFree4merWT
LampFree5merWT LampFree6merWT LampFree7merWT LampFree8merWT
WTasyn8merBindOnLamp WTasyn3merBindOnLamp WTasyn4merBindOnLamp WTasyn6merBindOnLamp
DopModWTasynCMAInhibition M/autophagyDopModWTasyn4Degr M/autophagyDopModWTasyn3Degr M/autophagyDopModWTasyn2Degr
M/autophagyDopModWTasyn5Degr M/autophagyDopModWTasyn6Degr M/autophagyDopModWTasyn7Degr M/autophagyDopModWTasyn8Degr
WTasyn2merFormOnLamp WTasyn3merFormOnLamp WTasyn4merFormOnLamp WTasyn5merFormOnLamp
WTasyn6merFormOnLamp WTasyn7merFormOnLamp WTasyn8merFormOnLamp WTasyn9merFormOnLamp
ProtFree3merWT ProtFree4merWT ProtFree5merWT ProtFree6merWT
ProtFree7merWT ProtFree8merWT ProtFree9merWT ProtFree3merDopWT
ProtFree4merDopWT ProtFree5merDopWT ProtFree6merDopWT ProtFree7merDopWT
ProtFree8merDopWT ProtFree9merDopWT WTasynHigherPSCprotInh DopMod9merDis
DopMod8merDis DopMod7merDis DopMod6merDis DopMod4merDis
DopMod5merDis DopMod3merDis DopMod2merDis 9merDis
8merDis 7merDis 6merDis 5merDis
4merDis 3merDis 2merDis AggregGrowth
AutophagosomeUptakeWTasyn M/autophagyWTasyn1Degr DopModAutophagosomeUptake M/autophagyDopModWTasyn1Degr
Rules
Assignment Rule (variable: Total_Cytosolic_WTASYN_Dimer) Assignment Rule (variable: Total_Cytosolic_WTASYN_Monomer) Assignment Rule (variable: Total_Cytosolic_WTASYN_Oligomers)  
Physical entities
Compartments Species
Lysosome Lamp2a WTasyn WTasyn2
WTasyndegr WTasyn2degr WTasyn2merCMADegr
WTasynCMADegr DopModWTasyn2merOnLamp DopModWTasyn3merOnLamp
DopModWTasyn4merOnLamp DopModWTasyn7merOnLamp DopModWTasyn6merOnLamp
DopModWTasyn5merOnLamp DopModWTasyn8merOnLamp DopModWTasyn9merOnLamp
WTasyn3merOnLamp WTasyn4merOnLamp WTasyn5merOnLamp
WTasyn6merOnLamp WTasyn7merOnLamp WTasyn8merOnLamp
WTasyn9merOnLamp DopModWTasynOnLamp  
M/autophagy&OtherLysDegrPath WTasyn2merM/Adegr WTasyn3merM/Adegr WTasyn4merM/Adegrr
WTasyn5merM/Adegr WTasyn6merM/Adegr WTasyn7merM/Adegr
WTasyn8merM/Adegr DopModWTasyn2merM/Adegr DopModWTasyn3merM/Adegr
DopModWTasyn4merM/Adegr DopModWTasyn6merM/Adegr DopModWTasyn8merM/Adegr
WTasyn4 WTasyn5 WTasyn6
WTasyn3 WTasyn2 WTasyn7
WTasyn8 DopModWTasyn7merM/Adegr DopModWTasyn8
DopModWTasyn7 DopModWTasyn6 DopModWTasyn5
DopModWTasyn4 DopModWTasyn3 WTasyn
DopModWTasyn DopModWTasyn2  
Cytosol DopModWTasyn5 DopModWTasyn4 SOURCE
DopModWTasyn3 DopModWTasyn2 DopModWTasyn
WTasyn WTasyn2 WTasyn3
DopModWTasyn6 Dopamine WTasyn5
WTasyn4 DopModWTasyn7 DopModWTasyn8
DopModWTasyn9 WTasyn9 WTasyn8
WTasyn7 WTasyn6 HigherWTasynSPC
Proteasome Dopamine_degraded ProtWTasyn3
ProtWTasyn4 ProtWTasyn5 ProtWTasyn6
ProtWTasyn7 ProtWTasyn8 ProtWTasyn9
ProtDopModWTasyn3 ProtDopModWTasyn4 ProtDopModWTasyn5
ProtDopModWTasyn6 ProtDopModWTasyn7 ProtDopModWTasyn8
ProtDopModWTasyn9 ProtWTasynHigherSPC  
Global parameters
k_DisRate k_2merForm k_DopModWTasynLampBind k_LampFreeWTasyn
k_OligAutophagUptake k_OligomerForm k_ProteasomeBind k_ProtOligDegr
k_WTasyn1_2merBindOnLamp k_WTOligBindOnLamp Total_Cytosolic_WTASYN_Oligomers Total_Cytosolic_WTASYN_Monomer
Total_Cytosolic_WTASYN_Dimer k_M_autophagyDegr    
Reactions (136)
 
 WTasynSynthesis [SOURCE] → [WTasyn];   {SOURCE}
 
 DopProduction [SOURCE] → [Dopamine];   {SOURCE}
 
 2merForm 2.0 × [WTasyn] → [WTasyn2];   {WTasyn}
 
 WTasynDopModification [WTasyn] + [Dopamine] → [DopModWTasyn];   {WTasyn} , {Dopamine}
 
 WTasynLampBind [WTasyn] + [Lamp2a] → [WTasyndegr];   {WTasyn} , {Lamp2a}
 
 AutophagosomeUptakeWTasyn2mer [WTasyn2] → [WTasyn2];   {WTasyn2}
 
 3merForm [WTasyn2] + [WTasyn] → [WTasyn3];   {WTasyn2} , {WTasyn}
 
 WTasyn2LampBind [WTasyn2] + [Lamp2a] → [WTasyn2degr];   {WTasyn2} , {Lamp2a}
 
 AutophagosomeUptakeWTasyn3mer [WTasyn3] → [WTasyn3];   {WTasyn3}
 
 4merForm [WTasyn3] + [WTasyn] → [WTasyn4];   {WTasyn3} , {WTasyn}
 
 3merProtBind [WTasyn3] + [Proteasome] → [ProtWTasyn3];   {WTasyn3} , {Proteasome}
 
 AutophagosomeUptakeWTasyn4mer [WTasyn4] → [WTasyn4];   {WTasyn4}
 
 5merForm [WTasyn4] + [WTasyn] → [WTasyn5];   {WTasyn4} , {WTasyn}
 
 4merProtBind [WTasyn4] + [Proteasome] → [ProtWTasyn4];   {WTasyn4} , {Proteasome}
 
 AutophagosomeUptakeWTasyn5mer [WTasyn5] → [WTasyn5];   {WTasyn5}
 
 6merForm [WTasyn5] + [WTasyn] → [WTasyn6];   {WTasyn5} , {WTasyn}
 
 5merProtBind [WTasyn5] + [Proteasome] → [ProtWTasyn5];   {WTasyn5} , {Proteasome}
 
 WTasyn5merBindOnLamp [WTasyn5] + [Lamp2a] → [WTasyn5merOnLamp];   {WTasyn5} , {Lamp2a}
 
 AutophagosomeUptakeWTasyn6mer [WTasyn6] → [WTasyn6];   {WTasyn6}
 
 7merForm [WTasyn6] + [WTasyn] → [WTasyn7];   {WTasyn6} , {WTasyn}
 
 6merProtBind [WTasyn6] + [Proteasome] → [ProtWTasyn6];   {WTasyn6} , {Proteasome}
 
 AutophagosomeUptakeWTasyn7mer [WTasyn7] → [WTasyn7];   {WTasyn7}
 
 8merForm [WTasyn7] + [WTasyn] → [WTasyn8];   {WTasyn7} , {WTasyn}
 
 7merProtBind [WTasyn7] + [Proteasome] → [ProtWTasyn7];   {WTasyn7} , {Proteasome}
 
 WTasyn7merBindOnLamp [WTasyn7] + [Lamp2a] → [WTasyn7merOnLamp];   {WTasyn7} , {Lamp2a}
 
 AutophagosomeUptakeWTasyn8mer [WTasyn8] → [WTasyn8];   {WTasyn8}
 
 9merForm [WTasyn8] + [WTasyn] → [WTasyn9];   {WTasyn8} , {WTasyn}
 
 8merProtBind [WTasyn8] + [Proteasome] → [ProtWTasyn8];   {WTasyn8} , {Proteasome}
 
 9merProtBind [WTasyn9] + [Proteasome] → [ProtWTasyn9];   {WTasyn9} , {Proteasome}
 
 WTasyn9merBindOnLamp [WTasyn9] + [Lamp2a] → [WTasyn9merOnLamp];   {WTasyn9} , {Lamp2a}
 
 DopamineDegr [Dopamine] → [Dopamine_degraded];   {Dopamine}
 
 DopMod2merForm 2.0 × [DopModWTasyn] → [DopModWTasyn2];   {DopModWTasyn}
 
 DopWTasyn2merFormOnLamp [DopModWTasyn] + [DopModWTasynOnLamp] → [DopModWTasyn2merOnLamp];   {DopModWTasyn} , {DopModWTasynOnLamp}
 
 DopWTasyn7merFormOnLamp [DopModWTasyn] + [DopModWTasyn6merOnLamp] → [DopModWTasyn7merOnLamp];   {DopModWTasyn} , {DopModWTasyn6merOnLamp}
 
 DopWTasyn8merFormOnLamp [DopModWTasyn] + [DopModWTasyn7merOnLamp] → [DopModWTasyn8merOnLamp];   {DopModWTasyn} , {DopModWTasyn7merOnLamp}
 
 DopWTasyn9merFormOnLamp [DopModWTasyn] + [DopModWTasyn8merOnLamp] → [DopModWTasyn9merOnLamp];   {DopModWTasyn} , {DopModWTasyn8merOnLamp}
 
 WTasynLysosUptake [WTasyndegr] → [Lamp2a] + [WTasyn];   {WTasyndegr}
 
 WTasyn2LysosUptake [WTasyn2degr] → [Lamp2a] + [WTasyn2];   {WTasyn2degr}
 
 M/autophagyWTasyn4Degr [WTasyn4] → [WTasyn4merM/Adegrr];   {WTasyn4}
 
 M/autophagyWTasyn8Degr [WTasyn8] → [WTasyn8merM/Adegr];   {WTasyn8}
 
 M/autophagyWTasyn3Degr [WTasyn3] → [WTasyn3merM/Adegr];   {WTasyn3}
 
 M/autophagyWTasyn2Degr [WTasyn2] → [WTasyn2merM/Adegr];   {WTasyn2}
 
 M/autophagyWTasyn7Degr [WTasyn7] → [WTasyn7merM/Adegr];   {WTasyn7}
 
 M/autophagyWTasyn5Degr [WTasyn5] → [WTasyn5merM/Adegr];   {WTasyn5}
 
 M/autophagyWTasyn6Degr [WTasyn6] → [WTasyn6merM/Adegr];   {WTasyn6}
 
 AggregForm [WTasyn9] + [WTasyn] → [HigherWTasynSPC];   {WTasyn9} , {WTasyn}
 
 DopModAutophagosomeUptake2mer [DopModWTasyn2] → [DopModWTasyn2];   {DopModWTasyn2}
 
 DopMod3merForm [DopModWTasyn2] + [DopModWTasyn] → [DopModWTasyn3];   {DopModWTasyn2} , {DopModWTasyn}
 
 DopModAutophagosomeUptake3mer [DopModWTasyn3] → [DopModWTasyn3];   {DopModWTasyn3}
 
 DopMod4merForm [DopModWTasyn3] + [DopModWTasyn] → [DopModWTasyn4];   {DopModWTasyn3} , {DopModWTasyn}
 
 DopMod3merProtBind [DopModWTasyn3] + [Proteasome] → [ProtDopModWTasyn3];   {DopModWTasyn3} , {Proteasome}
 
 DopModAutophagosomeUptake4mer [DopModWTasyn4] → [DopModWTasyn4];   {DopModWTasyn4}
 
 DopMod5merForm [DopModWTasyn4] + [DopModWTasyn] → [DopModWTasyn5];   {DopModWTasyn4} , {DopModWTasyn}
 
 DopMod4merProtBind [DopModWTasyn4] + [Proteasome] → [ProtDopModWTasyn4];   {DopModWTasyn4} , {Proteasome}
 
 DopModAutophagosomeUptake5mer [DopModWTasyn5] → [DopModWTasyn5];   {DopModWTasyn5}
 
 DopMod6merForm [DopModWTasyn5] + [DopModWTasyn] → [DopModWTasyn6];   {DopModWTasyn5} , {DopModWTasyn}
 
 DopMod5merProtBind [DopModWTasyn5] + [Proteasome] → [ProtDopModWTasyn5];   {DopModWTasyn5} , {Proteasome}
 
 DopModAutophagosomeUptake6mer [DopModWTasyn6] → [DopModWTasyn6];   {DopModWTasyn6}
 
 DopMod7merForm [DopModWTasyn6] + [DopModWTasyn] → [DopModWTasyn7];   {DopModWTasyn6} , {DopModWTasyn}
 
 DopMod6merProtBind [DopModWTasyn6] + [Proteasome] → [ProtDopModWTasyn6];   {DopModWTasyn6} , {Proteasome}
 
 DopModAutophagosomeUptake7mer [DopModWTasyn7] → [DopModWTasyn7];   {DopModWTasyn7}
 
 DopMod8merForm [DopModWTasyn7] + [DopModWTasyn] → [DopModWTasyn8];   {DopModWTasyn7} , {DopModWTasyn}
 
 DopMod7merProtBind [DopModWTasyn7] + [Proteasome] → [ProtDopModWTasyn7];   {DopModWTasyn7} , {Proteasome}
 
 DopModAutophagosomeUptake8mer [DopModWTasyn8] → [DopModWTasyn8];   {DopModWTasyn8}
 
 DopMod9merForm [DopModWTasyn8] + [DopModWTasyn] → [DopModWTasyn9];   {DopModWTasyn8} , {DopModWTasyn}
 
 DopMod8merProtBind [DopModWTasyn8] + [Proteasome] → [ProtDopModWTasyn8];   {DopModWTasyn8} , {Proteasome}
 
 DopMod9merProtBind [DopModWTasyn9] + [Proteasome] → [ProtDopModWTasyn9];   {DopModWTasyn9} , {Proteasome}
 
 WTasyn2merCMADegr [WTasyn2] → [WTasyn2merCMADegr];   {WTasyn2}
 
 WTasyn1merCMADegr [WTasyn] → [WTasynCMADegr];   {WTasyn}
 
 LampFree9merWT [WTasyn9merOnLamp] → [WTasyn9] + [Lamp2a];   {WTasyn9merOnLamp}
 
 DopWTasyn3merFormOnLamp [DopModWTasyn2merOnLamp] + [DopModWTasyn] → [DopModWTasyn3merOnLamp];   {DopModWTasyn2merOnLamp} , {DopModWTasyn}
 
 DopWTasyn4merFormOnLamp [DopModWTasyn3merOnLamp] + [DopModWTasyn] → [DopModWTasyn4merOnLamp];   {DopModWTasyn3merOnLamp} , {DopModWTasyn}
 
 DopWTasyn5merFormOnLamp [DopModWTasyn4merOnLamp] + [DopModWTasyn] → [DopModWTasyn5merOnLamp];   {DopModWTasyn4merOnLamp} , {DopModWTasyn}
 
 DopWTasyn6merFormOnLamp [DopModWTasyn5merOnLamp] + [DopModWTasyn] → [DopModWTasyn6merOnLamp];   {DopModWTasyn5merOnLamp} , {DopModWTasyn}
 
 LampFree3merWT [WTasyn3merOnLamp] → [WTasyn3] + [Lamp2a];   {WTasyn3merOnLamp}
 
 LampFree4merWT [WTasyn4merOnLamp] → [WTasyn4] + [Lamp2a];   {WTasyn4merOnLamp}
 
 LampFree5merWT [WTasyn5merOnLamp] → [WTasyn5] + [Lamp2a];   {WTasyn5merOnLamp}
 
 LampFree6merWT [WTasyn6merOnLamp] → [WTasyn6] + [Lamp2a];   {WTasyn6merOnLamp}
 
 LampFree7merWT [WTasyn7merOnLamp] → [WTasyn7] + [Lamp2a];   {WTasyn7merOnLamp}
 
 LampFree8merWT [WTasyn8merOnLamp] → [WTasyn8] + [Lamp2a];   {WTasyn8merOnLamp}
 
 WTasyn8merBindOnLamp [WTasyn8merOnLamp] + [WTasyn8] → [Lamp2a];   {WTasyn8merOnLamp} , {WTasyn8}
 
 WTasyn3merBindOnLamp [Lamp2a] + [WTasyn3] → [WTasyn3merOnLamp];   {Lamp2a} , {WTasyn3}
 
 WTasyn4merBindOnLamp [Lamp2a] + [WTasyn4] → [WTasyn4merOnLamp];   {Lamp2a} , {WTasyn4}
 
 WTasyn6merBindOnLamp [Lamp2a] + [WTasyn6] → [WTasyn6merOnLamp];   {Lamp2a} , {WTasyn6}
 
 DopModWTasynCMAInhibition [Lamp2a] + [DopModWTasyn] → [DopModWTasynOnLamp];   {Lamp2a} , {DopModWTasyn}
 
 M/autophagyDopModWTasyn4Degr [DopModWTasyn4] → [DopModWTasyn4merM/Adegr];   {DopModWTasyn4}
 
 M/autophagyDopModWTasyn3Degr [DopModWTasyn3] → [DopModWTasyn3merM/Adegr];   {DopModWTasyn3}
 
 M/autophagyDopModWTasyn2Degr [DopModWTasyn2] → [DopModWTasyn2merM/Adegr];   {DopModWTasyn2}
 
 M/autophagyDopModWTasyn5Degr [DopModWTasyn5] → [DopModWTasyn6merM/Adegr];   {DopModWTasyn5}
 
 M/autophagyDopModWTasyn6Degr [DopModWTasyn6] → [DopModWTasyn7merM/Adegr];   {DopModWTasyn6}
 
 M/autophagyDopModWTasyn7Degr [DopModWTasyn7] → [DopModWTasyn7merM/Adegr];   {DopModWTasyn7}
 
 M/autophagyDopModWTasyn8Degr [DopModWTasyn8] → [DopModWTasyn8merM/Adegr];   {DopModWTasyn8}
 
 WTasyn2merFormOnLamp [WTasyn] + [WTasyndegr] → [WTasyn2degr];   {WTasyn} , {WTasyndegr}
 
 WTasyn3merFormOnLamp [WTasyn] + [WTasyn2degr] → [WTasyn3merOnLamp];   {WTasyn} , {WTasyn2degr}
 
 WTasyn4merFormOnLamp [WTasyn] + [WTasyn3merOnLamp] → [WTasyn4merOnLamp];   {WTasyn} , {WTasyn3merOnLamp}
 
 WTasyn5merFormOnLamp [WTasyn] + [WTasyn4merOnLamp] → [WTasyn5merOnLamp];   {WTasyn} , {WTasyn4merOnLamp}
 
 WTasyn6merFormOnLamp [WTasyn5merOnLamp] + [WTasyn] → [WTasyn6merOnLamp];   {WTasyn5merOnLamp} , {WTasyn}
 
 WTasyn7merFormOnLamp [WTasyn6merOnLamp] + [WTasyn] → [WTasyn7merOnLamp];   {WTasyn6merOnLamp} , {WTasyn}
 
 WTasyn8merFormOnLamp [WTasyn] + [WTasyn7merOnLamp] → [WTasyn8merOnLamp];   {WTasyn} , {WTasyn7merOnLamp}
 
 WTasyn9merFormOnLamp [WTasyn] + [WTasyn8merOnLamp] → [WTasyn9merOnLamp];   {WTasyn} , {WTasyn8merOnLamp}
 
 ProtFree3merWT [ProtWTasyn3] → [Proteasome];   {ProtWTasyn3}
 
 ProtFree4merWT [ProtWTasyn4] → [Proteasome];   {ProtWTasyn4}
 
 ProtFree5merWT [ProtWTasyn5] → [Proteasome];   {ProtWTasyn5}
 
 ProtFree6merWT [ProtWTasyn6] → [Proteasome];   {ProtWTasyn6}
 
 ProtFree7merWT [ProtWTasyn7] → [Proteasome];   {ProtWTasyn7}
 
 ProtFree8merWT [ProtWTasyn8] → [Proteasome];   {ProtWTasyn8}
 
 ProtFree9merWT [ProtWTasyn9] → [Proteasome];   {ProtWTasyn9}
 
 ProtFree3merDopWT [ProtDopModWTasyn3] → [Proteasome];   {ProtDopModWTasyn3}
 
 ProtFree4merDopWT [ProtDopModWTasyn4] → [Proteasome];   {ProtDopModWTasyn4}
 
 ProtFree5merDopWT [ProtDopModWTasyn5] → [Proteasome];   {ProtDopModWTasyn5}
 
 ProtFree6merDopWT [ProtDopModWTasyn6] → [Proteasome];   {ProtDopModWTasyn6}
 
 ProtFree7merDopWT [ProtDopModWTasyn7] → [Proteasome];   {ProtDopModWTasyn7}
 
 ProtFree8merDopWT [ProtDopModWTasyn8] → [Proteasome];   {ProtDopModWTasyn8}
 
 ProtFree9merDopWT [ProtDopModWTasyn9] → [Proteasome];   {ProtDopModWTasyn9}
 
 WTasynHigherPSCprotInh [HigherWTasynSPC] + [Proteasome] → [ProtWTasynHigherSPC];   {HigherWTasynSPC} , {Proteasome}
 
 DopMod9merDis [DopModWTasyn9] → [DopModWTasyn8] + [DopModWTasyn];   {DopModWTasyn9}
 
 DopMod8merDis [DopModWTasyn8] → [DopModWTasyn7] + [DopModWTasyn];   {DopModWTasyn8}
 
 DopMod7merDis [DopModWTasyn7] → [DopModWTasyn6] + [DopModWTasyn];   {DopModWTasyn7}
 
 DopMod6merDis [DopModWTasyn6] → [DopModWTasyn5] + [DopModWTasyn];   {DopModWTasyn6}
 
 DopMod4merDis [DopModWTasyn4] → [DopModWTasyn3] + [DopModWTasyn];   {DopModWTasyn4}
 
 DopMod5merDis [DopModWTasyn5] → [DopModWTasyn4] + [DopModWTasyn];   {DopModWTasyn5}
 
 DopMod3merDis [DopModWTasyn3] → [DopModWTasyn2] + [DopModWTasyn];   {DopModWTasyn3}
 
 DopMod2merDis [DopModWTasyn2] → 2.0 × [DopModWTasyn];   {DopModWTasyn2}
 
 9merDis [WTasyn9] → [WTasyn] + [WTasyn8];   {WTasyn9}
 
 8merDis [WTasyn8] → [WTasyn7] + [WTasyn];   {WTasyn8}
 
 7merDis [WTasyn7] → [WTasyn6] + [WTasyn];   {WTasyn7}
 
 6merDis [WTasyn6] → [WTasyn] + [WTasyn5];   {WTasyn6}
 
 5merDis [WTasyn5] → [WTasyn4] + [WTasyn];   {WTasyn5}
 
 4merDis [WTasyn4] → [WTasyn3] + [WTasyn];   {WTasyn4}
 
 3merDis [WTasyn3] → [WTasyn2] + [WTasyn];   {WTasyn3}
 
 2merDis [WTasyn2] → 2.0 × [WTasyn];   {WTasyn2}
 
 AggregGrowth [HigherWTasynSPC] + [WTasyn] → [HigherWTasynSPC];   {HigherWTasynSPC} , {WTasyn}
 
 AutophagosomeUptakeWTasyn [WTasyn] → [WTasyn];   {WTasyn}
 
 M/autophagyWTasyn1Degr [WTasyn] → [WTasyn2merM/Adegr];   {WTasyn}
 
 DopModAutophagosomeUptake [DopModWTasyn] → [DopModWTasyn];   {DopModWTasyn}
 
 M/autophagyDopModWTasyn1Degr [DopModWTasyn] → [DopModWTasyn2merM/Adegr];   {DopModWTasyn}
 
Rules (3)
 
 Assignment Rule (name: Total_Cytosolic_WTASYN_Dimer) Total_Cytosolic_WTASYN_Dimer = s6*c1+s18*c1
 
 Assignment Rule (name: Total_Cytosolic_WTASYN_Monomer) Total_Cytosolic_WTASYN_Monomer = s17*c1+s7*c1
 
 Assignment Rule (name: Total_Cytosolic_WTASYN_Oligomers) Total_Cytosolic_WTASYN_Oligomers = s5*c1+s2*c1+s1*c1+s21*c1+s25*c1+s26*c1+s27*c1+s20*c1+s24*c1+s23*c1+s32*c1+s31*c1+s30*c1+s29*c1
 
 Lysosome Spatial dimensions: 3.0  Compartment size: 1.0
 
 Lamp2a
Compartment: Lysosome
Initial amount: 200.0
 
 WTasyn
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn2
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyndegr
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn2degr
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn2merCMADegr
Compartment: Lysosome
Initial amount: 0.0
 
 WTasynCMADegr
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasyn2merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasyn3merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasyn4merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasyn7merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasyn6merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasyn5merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasyn8merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasyn9merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn3merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn4merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn5merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn6merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn7merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn8merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 WTasyn9merOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 DopModWTasynOnLamp
Compartment: Lysosome
Initial amount: 0.0
 
 M/autophagy&OtherLysDegrPath Spatial dimensions: 3.0  Compartment size: 1.0
 
 WTasyn2merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn3merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn4merM/Adegrr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn5merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn6merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn7merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn8merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn2merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn3merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn4merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn6merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn8merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn4
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn5
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn6
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn3
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn2
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn7
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn8
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn7merM/Adegr
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn8
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn7
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn6
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn5
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn4
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn3
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 WTasyn
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 DopModWTasyn2
Compartment: M/autophagy&OtherLysDegrPath
Initial amount: 0.0
 
 Cytosol Spatial dimensions: 3.0  Compartment size: 1.0
 
 DopModWTasyn5
Compartment: Cytosol
Initial amount: 8.0
 
 DopModWTasyn4
Compartment: Cytosol
Initial amount: 8.0
 
 SOURCE
Compartment: Cytosol
Initial amount: 1.0
Constant
 
 DopModWTasyn3
Compartment: Cytosol
Initial amount: 8.0
 
 DopModWTasyn2
Compartment: Cytosol
Initial amount: 0.0
 
 DopModWTasyn
Compartment: Cytosol
Initial amount: 953.0
 
 WTasyn
Compartment: Cytosol
Initial amount: 1650.0
 
 WTasyn2
Compartment: Cytosol
Initial amount: 22.0
 
 WTasyn3
Compartment: Cytosol
Initial amount: 8.0
 
 DopModWTasyn6
Compartment: Cytosol
Initial amount: 8.0
 
 Dopamine
Compartment: Cytosol
Initial amount: 750.0
 
 WTasyn5
Compartment: Cytosol
Initial amount: 8.0
 
 WTasyn4
Compartment: Cytosol
Initial amount: 8.0
 
 DopModWTasyn7
Compartment: Cytosol
Initial amount: 8.0
 
 DopModWTasyn8
Compartment: Cytosol
Initial amount: 8.0
 
 DopModWTasyn9
Compartment: Cytosol
Initial amount: 8.0
 
 WTasyn9
Compartment: Cytosol
Initial amount: 8.0
 
 WTasyn8
Compartment: Cytosol
Initial amount: 8.0
 
 WTasyn7
Compartment: Cytosol
Initial amount: 8.0
 
 WTasyn6
Compartment: Cytosol
Initial amount: 8.0
 
 HigherWTasynSPC
Compartment: Cytosol
Initial amount: 0.0
 
 Proteasome
Compartment: Cytosol
Initial amount: 1500.0
 
 Dopamine_degraded
Compartment: Cytosol
Initial amount: 0.0
 
 ProtWTasyn3
Compartment: Cytosol
Initial amount: 0.0
 
 ProtWTasyn4
Compartment: Cytosol
Initial amount: 0.0
 
 ProtWTasyn5
Compartment: Cytosol
Initial amount: 0.0
 
 ProtWTasyn6
Compartment: Cytosol
Initial amount: 0.0
 
 ProtWTasyn7
Compartment: Cytosol
Initial amount: 0.0
 
 ProtWTasyn8
Compartment: Cytosol
Initial amount: 0.0
 
 ProtWTasyn9
Compartment: Cytosol
Initial amount: 0.0
 
 ProtDopModWTasyn3
Compartment: Cytosol
Initial amount: 0.0
 
 ProtDopModWTasyn4
Compartment: Cytosol
Initial amount: 0.0
 
 ProtDopModWTasyn5
Compartment: Cytosol
Initial amount: 0.0
 
 ProtDopModWTasyn6
Compartment: Cytosol
Initial amount: 0.0
 
 ProtDopModWTasyn7
Compartment: Cytosol
Initial amount: 0.0
 
 ProtDopModWTasyn8
Compartment: Cytosol
Initial amount: 0.0
 
 ProtDopModWTasyn9
Compartment: Cytosol
Initial amount: 0.0
 
 ProtWTasynHigherSPC
Compartment: Cytosol
Initial amount: 0.0
 
Global Parameters (14)
 
 k_DisRate
Value: 4.999533748E-7
Constant
 
   k_2merForm
Value: 1.462941015E-9
Constant
 
   k_DopModWTasynLampBind
Value: 7.6715997E-9
Constant
 
   k_LampFreeWTasyn
Value: 3.044571674E-4
Constant
 
   k_OligAutophagUptake
Value: 2.39034347E-8
Constant
 
   k_OligomerForm
Value: 3.350497192E-8
Constant
 
   k_ProteasomeBind
Value: 3.424693672E-9
Constant
 
   k_ProtOligDegr
Value: 3.70096E-4
Constant
 
   k_WTasyn1_2merBindOnLamp
Value: 6.865455081E-7
Constant
 
   k_WTOligBindOnLamp
Value: 4.0E-6
Constant
 
   Total_Cytosolic_WTASYN_Oligomers
Value: 112.0
 
   Total_Cytosolic_WTASYN_Monomer
Value: 2603.0
 
   Total_Cytosolic_WTASYN_Dimer
Value: 22.0
 
   k_M_autophagyDegr
Value: 0.1
Constant
 
WTasynSynthesis (1)
 
   k1
Value: 0.0294219
Constant
 
DopProduction (1)
 
   k1
Value: 0.0791823
Constant
 
WTasynDopModification (1)
 
   k1
Value: 6.74768E-7
Constant
 
DopamineDegr (1)
 
   k1
Value: 0.00679501
Constant
 
WTasynLysosUptake (1)
 
   k1
Value: 0.00999558
Constant
 
WTasyn2LysosUptake (1)
 
   k1
Value: 0.00995312
Constant
 
WTasyn2merCMADegr (1)
 
   k1
Value: 0.1
Constant
 
WTasyn1merCMADegr (1)
 
   k1
Value: 0.1
Constant
 
AggregGrowth (1)
 
   k1
Value: 4.90556E-7
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000559

Curator's comment: (updated: 09 Dec 2014 14:42:40 GMT)

Figure 7 of Supplementary material 5 (derived from Figure 5 of the reference publication) has been reproduced here. Dynamics of several alpha-synuclein conformations are simulated during 7 days (600000 seconds).

The simulation was done using SBML odeSolver. The plot were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link:

Additional file(s)
  • Ouzounoglou2014 - Modeling of alpha-synuclein effects on neuronal homeostasis:
    Copasi file of the model
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