re1
WTasynSynthesis
s3 > s17
re10
4merForm
s20 + s17 > s24
re100
WTasyn8merFormOnLamp
s17 + s499 > s500
re101
WTasyn9merFormOnLamp
s17 + s500 > s501
re102
ProtFree3merWT
s381 > s35
re103
ProtFree4merWT
s383 > s35
re104
ProtFree5merWT
s385 > s35
re105
ProtFree6merWT
s387 > s35
re106
ProtFree7merWT
s389 > s35
re107
ProtFree8merWT
s391 > s35
re108
ProtFree9merWT
s393 > s35
re109
ProtFree3merDopWT
s473 > s35
re11
3merProtBind
s20 + s35 > s381
re110
ProtFree4merDopWT
s474 > s35
re111
ProtFree5merDopWT
s475 > s35
re112
ProtFree6merDopWT
s476 > s35
re113
ProtFree7merDopWT
s477 > s35
re114
ProtFree8merDopWT
s478 > s35
re115
ProtFree9merDopWT
s479 > s35
re116
WTasynHigherPSCprotInh
s33 + s35 > s502
re117
DopMod9merDis
s27 > s26 + s7
re118
DopMod8merDis
s26 > s25 + s7
re119
DopMod7merDis
s25 > s21 + s7
re12
AutophagosomeUptakeWTasyn4mer
s24 > s517
re120
DopMod6merDis
s21 > s1 + s7
re121
DopMod4merDis
s2 > s5 + s7
re122
DopMod5merDis
s1 > s2 + s7
re123
DopMod3merDis
s5 > s6 + s7
re124
DopMod2merDis
s6 > {2.0}s7
re125
9merDis
s29 > s17 + s30
re126
8merDis
s30 > s31 + s17
re127
7merDis
s31 > s32 + s17
re128
6merDis
s32 > s17 + s23
re129
5merDis
s23 > s24 + s17
re13
5merForm
s24 + s17 > s23
re130
4merDis
s24 > s20 + s17
re131
3merDis
s20 > s18 + s17
re132
2merDis
s18 > {2.0}s17
re133
AggregGrowth
s33 + s17 > s33
re134
AutophagosomeUptakeWTasyn
s17 > s533
re135
M/autophagyWTasyn1Degr
s533 > s107
re136
DopModAutophagosomeUptake
s7 > s535
re137
M/autophagyDopModWTasyn1Degr
s535 > s445
re14
4merProtBind
s24 + s35 > s383
re15
AutophagosomeUptakeWTasyn5mer
s23 > s518
re16
6merForm
s23 + s17 > s32
re17
5merProtBind
s23 + s35 > s385
re18
WTasyn5merBindOnLamp
s23 + s51 > s496
re19
AutophagosomeUptakeWTasyn6mer
s32 > s519
re2
DopProduction
s3 > s22
re20
7merForm
s32 + s17 > s31
re21
6merProtBind
s32 + s35 > s387
re22
AutophagosomeUptakeWTasyn7mer
s31 > s522
re23
8merForm
s31 + s17 > s30
re24
7merProtBind
s31 + s35 > s389
re25
WTasyn7merBindOnLamp
s31 + s51 > s499
re26
AutophagosomeUptakeWTasyn8mer
s30 > s523
re27
9merForm
s30 + s17 > s29
re28
8merProtBind
s30 + s35 > s391
re29
9merProtBind
s29 + s35 > s393
re3
2merForm
{2.0}s17 > s18
re30
WTasyn9merBindOnLamp
s29 + s51 > s501
re31
DopamineDegr
s22 > s200
re32
DopMod2merForm
{2.0}s7 > s6
re33
DopWTasyn2merFormOnLamp
s7 + s536 > s482
re34
DopWTasyn7merFormOnLamp
s7 + s490 > s489
re35
DopWTasyn8merFormOnLamp
s7 + s489 > s492
re36
DopWTasyn9merFormOnLamp
s7 + s492 > s493
re37
WTasynLysosUptake
s78 > s51 + s52
re38
WTasyn2LysosUptake
s85 > s51 + s53
re4
WTasynDopModification
s17 + s22 > s7
re40
M/autophagyWTasyn4Degr
s517 > s109
re41
M/autophagyWTasyn8Degr
s523 > s113
re42
M/autophagyWTasyn3Degr
s520 > s108
re43
M/autophagyWTasyn2Degr
s521 > s107
re44
M/autophagyWTasyn7Degr
s522 > s112
re45
M/autophagyWTasyn5Degr
s518 > s110
re46
M/autophagyWTasyn6Degr
s519 > s111
re47
AggregForm
s29 + s17 > s33
re48
DopModAutophagosomeUptake2mer
s6 > s527
re49
DopMod3merForm
s6 + s7 > s5
re5
WTasynLampBind
s17 + s51 > s78
re50
DopModAutophagosomeUptake3mer
s5 > s531
re51
DopMod4merForm
s5 + s7 > s2
re52
DopMod3merProtBind
s5 + s35 > s473
re53
DopModAutophagosomeUptake4mer
s2 > s530
re54
DopMod5merForm
s2 + s7 > s1
re55
DopMod4merProtBind
s2 + s35 > s474
re56
DopModAutophagosomeUptake5mer
s1 > s529
re57
DopMod6merForm
s1 + s7 > s21
re58
DopMod5merProtBind
s1 + s35 > s475
re59
DopModAutophagosomeUptake6mer
s21 > s528
re6
AutophagosomeUptakeWTasyn2mer
s18 > s521
re60
DopMod7merForm
s21 + s7 > s25
re61
DopMod6merProtBind
s21 + s35 > s476
re62
DopModAutophagosomeUptake7mer
s25 > s526
re63
DopMod8merForm
s25 + s7 > s26
re64
DopMod7merProtBind
s25 + s35 > s477
re65
DopModAutophagosomeUptake8mer
s26 > s525
re66
DopMod9merForm
s26 + s7 > s27
re67
DopMod8merProtBind
s26 + s35 > s478
re68
DopMod9merProtBind
s27 + s35 > s479
re69
WTasyn2merCMADegr
s53 > s211
re7
3merForm
s18 + s17 > s20
re70
WTasyn1merCMADegr
s52 > s213
re71
LampFree9merWT
s501 > s29 + s51
re72
DopWTasyn3merFormOnLamp
s482 + s7 > s483
re73
DopWTasyn4merFormOnLamp
s483 + s7 > s484
re74
DopWTasyn5merFormOnLamp
s484 + s7 > s491
re75
DopWTasyn6merFormOnLamp
s491 + s7 > s490
re76
LampFree3merWT
s494 > s20 + s51
re77
LampFree4merWT
s495 > s24 + s51
re78
LampFree5merWT
s496 > s23 + s51
re79
LampFree6merWT
s498 > s32 + s51
re8
WTasyn2LampBind
s18 + s51 > s85
re80
LampFree7merWT
s499 > s31 + s51
re81
LampFree8merWT
s500 > s30 + s51
re82
WTasyn8merBindOnLamp
s500 + s30 > s51
re83
WTasyn3merBindOnLamp
s51 + s20 > s494
re84
WTasyn4merBindOnLamp
s51 + s24 > s495
re85
WTasyn6merBindOnLamp
s51 + s32 > s498
re86
DopModWTasynCMAInhibition
s51 + s7 > s536
re87
M/autophagyDopModWTasyn4Degr
s530 > s447
re88
M/autophagyDopModWTasyn3Degr
s531 > s446
re89
M/autophagyDopModWTasyn2Degr
s527 > s445
re9
AutophagosomeUptakeWTasyn3mer
s20 > s520
re90
M/autophagyDopModWTasyn5Degr
s529 > s448
re91
M/autophagyDopModWTasyn6Degr
s528 > s524
re92
M/autophagyDopModWTasyn7Degr
s526 > s524
re93
M/autophagyDopModWTasyn8Degr
s525 > s451
re94
WTasyn2merFormOnLamp
s17 + s78 > s85
re95
WTasyn3merFormOnLamp
s17 + s85 > s494
re96
WTasyn4merFormOnLamp
s17 + s494 > s495
re97
WTasyn5merFormOnLamp
s17 + s495 > s496
re98
WTasyn6merFormOnLamp
s496 + s17 > s498
re99
WTasyn7merFormOnLamp
s498 + s17 > s499
Assignment rules
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
Total_Cytosolic_WTASYN_Monomer = s17 * c1 + s7 * c1
Total_Cytosolic_WTASYN_Dimer = s6 * c1 + s18 * c1
Function definitions
Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.
In silico modeling of the effects of alpha-synuclein oligomerization on dopaminergic neuronal homeostasis.
- PubMed: 24885905
- PubMed Central: PMC4062111
- DOI: 10.1186/1752-0509-8-54
- ISSN: 1752-0509
- URL: https://ncbi.nlm.nih.gov/pubmed/24885905
Abstract
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.