An in silico model of the ubiquitin-proteasome system that incorporates normal homeostasis and age-related decline |
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Authors: | Carole J Proctor Maria Tsirigotis Douglas A Gray |
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Institution: | (1) School of Clinical and Medical Sciences-Gerontology, Newcastle University, UK;(2) Centre for Integrated Systems Biology of Ageing and Nutrition, Newcastle University, UK;(3) Ottawa Health Research Institute, Ottawa, Canada;(4) Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada |
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Abstract: | Background The ubiquitin-proteasome system is responsible for homeostatic degradation of intact protein substrates as well as the elimination
of damaged or misfolded proteins that might otherwise aggregate. During ageing there is a decline in proteasome activity and
an increase in aggregated proteins. Many neurodegenerative diseases are characterised by the presence of distinctive ubiquitin-positive
inclusion bodies in affected regions of the brain. These inclusions consist of insoluble, unfolded, ubiquitinated polypeptides
that fail to be targeted and degraded by the proteasome. We are using a systems biology approach to try and determine the
primary event in the decline in proteolytic capacity with age and whether there is in fact a vicious cycle of inhibition,
with accumulating aggregates further inhibiting proteolysis, prompting accumulation of aggregates and so on. A stochastic
model of the ubiquitin-proteasome system has been developed using the Systems Biology Mark-up Language (SBML). Simulations
are carried out on the BASIS (Biology of Ageing e-Science Integration and Simulation) system and the model output is compared
to experimental data wherein levels of ubiquitin and ubiquitinated substrates are monitored in cultured cells under various
conditions. The model can be used to predict the effects of different experimental procedures such as inhibition of the proteasome
or shutting down the enzyme cascade responsible for ubiquitin conjugation. |
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