Overview

Oxidative stress occurs when excessive reactive oxygen products are produced more than the cellular mechanisms can absorb. This can occur by a number of mechanisms. For example, the MPTP based drugs that cause the end symptoms of PD (accumulation of Lewy bodies) are inducing significant oxidative stress and damage to α-synuclein in neurons. Elevated levels of iron have also been observed in the brains of Parkinson's sufferers and this in turn has been linked to increased oxidative stress and (potentially) the agglomeration of α-synuclein. Significant research addresses the use of iron chelators, thus preventing them from forming reactive oxidative products that may damaged proteins and cause oxidative stress. In a similar vein, excessive highly reactive molecules in the brain (free radicals) can cause cellular damage in part by oxidative stress. Links between dopamine metabolism and oxidative stress are also obvious, as dopamine can also cause oxidative stress if it is not correctly segregated by vesicles within the cellular environment.

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Research

The SoPD project considers oxidative stress in the mechanisms of disease development, as it is one of the most common stresses to affect biological systems and is highly relevant in the development of neurodegenerative diseases. The extrinsic mechanisms by which oxidative stress are generated are briefly discussed in the ‘toxins’ section. Intrinsic mechanisms could also be considered through the modelling of dopamine metabolism (see works by Qi, Miller and Voit). Cellular response to oxidative stress is also important. Pathways like the pentose phosphate shunt and glutathione metabolism are involved in the response to oxidative stress. The presence of oxidative molecules in abnormal concentrations is thus a sign not only of a stress, but also of an insufficient response of cellular defence systems. Regulation mechanisms allow switching between oxidative and non-oxidative metabolism in order to maintain critical cellular functions. The SoPD projects aims at elucidating these control mechanisms in a physiological context through a realistic integrative simulation.

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Contact point

• Prof. Peter Wellstead.

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Selected References

Qi Z., Miller G. W., Voit E. O. Computational Systems Analysis of Dopamine Metabolism. PLoS ONE, 3(6): e2444 (2008). doi:10.1371/journal.pone.0002444.

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