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Proctor2010 - UCHL1 Protein Aggregation

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  • 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
  • Center for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • 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.
Carole Proctor

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BIOMD0000000293.xml.origin SBML L2V3 representation of Proctor2010 - UCHL1 Protein Aggregation 235.92 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
  • 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
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.