Proctor2010 - UCHL1 Protein Aggregation

  public model
Model Identifier
BIOMD0000000293
Short description

This a model from the article:
Modelling the Role of UCH-L1 on Protein Aggregation in Age-Related Neurodegeneration.
Proctor CJ, Tangeman PJ, Ardley HC. PLoS One. 2010 Oct 6;5(10):e13175 20949132 ,
Abstract:
Overexpression of the de-ubiquitinating enzyme UCH-L1 leads to inclusion formation in response to proteasome impairment. These inclusions contain components of the ubiquitin-proteasome system and α-synuclein confirming that the ubiquitin-proteasome system plays an important role in protein aggregation. The processes involved are very complex and so we have chosen to take a systems biology approach to examine the system whereby we combine mathematical modelling with experiments in an iterative process. The experiments show that cells are very heterogeneous with respect to inclusion formation and so we use stochastic simulation. The model shows that the variability is partly due to stochastic effects but also depends on protein expression levels of UCH-L1 within cells. The model also indicates that the aggregation process can start even before any proteasome inhibition is present, but that proteasome inhibition greatly accelerates aggregation progression. This leads to less efficient protein degradation and hence more aggregation suggesting that there is a vicious cycle. However, proteasome inhibition may not necessarily be the initiating event. Our combined modelling and experimental approach show that stochastic effects play an important role in the aggregation process and could explain the variability in the age of disease onset. Furthermore, our model provides a valuable tool, as it can be easily modified and extended to incorporate new experimental data, test hypotheses and make testable predictions.


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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Format
SBML (L2V4)
Related Publication
  • Modelling the role of UCH-L1 on protein aggregation in age-related neurodegeneration.
  • Proctor CJ, Tangeman PJ, Ardley HC
  • PloS one , 10/ 2010 , Volume 5 , pages: e13175 , PubMed ID: 20949132
  • Center for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom. c.j.proctor@ncl.ac.uk
  • Overexpression of the de-ubiquitinating enzyme UCH-L1 leads to inclusion formation in response to proteasome impairment. These inclusions contain components of the ubiquitin-proteasome system and α-synuclein confirming that the ubiquitin-proteasome system plays an important role in protein aggregation. The processes involved are very complex and so we have chosen to take a systems biology approach to examine the system whereby we combine mathematical modelling with experiments in an iterative process. The experiments show that cells are very heterogeneous with respect to inclusion formation and so we use stochastic simulation. The model shows that the variability is partly due to stochastic effects but also depends on protein expression levels of UCH-L1 within cells. The model also indicates that the aggregation process can start even before any proteasome inhibition is present, but that proteasome inhibition greatly accelerates aggregation progression. This leads to less efficient protein degradation and hence more aggregation suggesting that there is a vicious cycle. However, proteasome inhibition may not necessarily be the initiating event. Our combined modelling and experimental approach show that stochastic effects play an important role in the aggregation process and could explain the variability in the age of disease onset. Furthermore, our model provides a valuable tool, as it can be easily modified and extended to incorporate new experimental data, test hypotheses and make testable predictions.
Contributors
Submitter of the first revision: Carole Proctor
Submitter of this revision: Carole Proctor
Modellers: Carole Proctor

Metadata information

is
BioModels Database MODEL0912070000
BioModels Database BIOMD0000000293
isDerivedFrom
BioModels Database BIOMD0000000105
isDescribedBy
PubMed 20949132
hasTaxon
Taxonomy Homo sapiens
isPartOf
KEGG Pathway Parkinson's disease
hasVersion
Human Disease Ontology neurodegenerative disease
hasProperty
Human Disease Ontology Parkinson's disease

Curation status
Curated

Original model(s)
Proctor_UCHL1_PD

Tags

Connected external resources

SBGN view in Newt Editor

Name Description Size Actions

Model files

BIOMD0000000293_url.xml SBML L2V4 representation of Proctor2010 - UCHL1 Protein Aggregation 355.35 KB Preview | Download

Additional files

BIOMD0000000293-biopax2.owl Auto-generated BioPAX (Level 2) 597.43 KB Preview | Download
BIOMD0000000293-biopax3.owl Auto-generated BioPAX (Level 3) 1.10 MB Preview | Download
BIOMD0000000293.m Auto-generated Octave file 105.02 KB Preview | Download
BIOMD0000000293.pdf Auto-generated PDF file 1.55 MB Preview | Download
BIOMD0000000293.png Auto-generated Reaction graph (PNG) 5.07 KB Preview | Download
BIOMD0000000293.sci Auto-generated Scilab file 70.50 KB Preview | Download
BIOMD0000000293.svg Auto-generated Reaction graph (SVG) 861.00 Bytes Preview | Download
BIOMD0000000293.vcml Auto-generated VCML file 549.11 KB Preview | Download
BIOMD0000000293.xpp Auto-generated XPP file 73.04 KB Preview | Download
BIOMD0000000293_urn.xml Auto-generated SBML file with URNs 350.88 KB Preview | Download

  • Model originally submitted by : Carole Proctor
  • Submitted: Dec 7, 2009 1:19:38 PM
  • Last Modified: Apr 8, 2016 5:54:30 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Apr 8, 2016 5:54:30 PM
    • Submitted by: Carole Proctor
    • With comment: Current version of Proctor2010 - UCHL1 Protein Aggregation
  • Version: 1 public model Download this version
    • Submitted on: Dec 7, 2009 1:19:38 PM
    • Submitted by: Carole Proctor
    • With comment: Original import of BIOMD0000000293.xml.origin

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Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
E3_MisP_Ub5 + SeqAggP => SeqAggP + aggMisP + aggUb + aggE3 kigrowth2*E3_MisP_Ub5*SeqAggP kigrowth2 = 5.0E-9
MisP_Ub7_Proteasome + DUB => MisP_Ub6_Proteasome + Ub + DUB kactDUBProt*MisP_Ub7_Proteasome*DUB kactDUBProt = 1.0E-6
E3_MisP_Ub_DUB => E3_MisP + DUB + Ub kactDUB*E3_MisP_Ub_DUB kactDUB = 1.0E-4
E3_MisP_Ub3_DUB + SeqAggP => SeqAggP + aggMisP + aggUb + aggE3 + aggDUB kigrowth2*E3_MisP_Ub3_DUB*SeqAggP kigrowth2 = 5.0E-9
AggP4 => AggP3 + MisP kdisagg4*AggP4 kdisagg4 = 4.0E-9
SUB_misfolded_Ub4_Proteasome + ATP => Ub + Proteasome + ADP kactProt*SUB_misfolded_Ub4_Proteasome*kproteff*ATP/(5000+ATP) kactProt = 0.01; kproteff = 1.0
E3SUB_SUB_misfolded_Ub + UCHL1 => E3SUB_SUB_misfolded_Ub_UCHL1 kbinSUBUCHL1*E3SUB_SUB_misfolded_Ub*UCHL1 kbinSUBUCHL1 = 4.0E-8
UCHL1_damaged + AggU2 => AggU3 kagg2dam*UCHL1_damaged*AggU2 kagg2dam = 0.005
AggU4 => AggU3 + UCHL1_damaged kdisagguchl1dam4*AggU4 kdisagguchl1dam4 = 4.0E-9
SeqAggP + UCHL1_damaged => SeqAggP + aggUchl1dam kigrowth1*SeqAggP*UCHL1_damaged kigrowth1 = 5.0E-9
Curator's comment:
(added: 10 Jan 2011, 13:49:21, updated: 10 Jan 2011, 13:49:21)
Figure 2 of the reference publication has been reproduced here. The model was integrated and simulated using Copasi v4.6 (Build 32). Stochastic (Gibson + Bruck) Method was used to simulated the model.