Diagram of the Systems of Parkinson's disease

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Diagram of the Systems of Parkinson's Disease Calcium signalling Cell system failure Drug treatment Visible symptoms Neuronal apoptosis Dopamine disorder Toxins Lewy bodies formation Electrical treatment Oxidative stress Faulty alpha-synuclein disposal Genetic disorders Energy metabolism failure

Toxins

Overview

Various studies have indicated a linkage between the incidence of PD and environmental toxins such as certain herbicides and pesticides associated with agriculture. The environmental toxins Paraquat, Rotenone and Maneb have been associated with causing cell death via damage to the cell mitochondria (see Bohlen et al. 2004). Studies have also linked the disease to solvents used in industrial processes and certain drugs. The search for environmental toxins was triggered by the discovery that drug addicts using preparations containing the chemical MPTP developed Parkinson type symptoms (Langston et al, 1983). In addition to environmental toxins, many substances that occur naturally in the body and have specific biological and physiological uses are, when they occur in excessive amounts at the wrong place and time, toxic. Dopamine, which is an important neurotransmitter for the regulation of movement and is involved in PD, is among those molecules that can cause oxidative stress. Thus a failure in the internal mechanisms that breakdown unwanted molecules or an excess number of normally useful molecules may also contribute to Parkinson's disease.

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Research

Toxins DiagramIn order to integrate the potential implications of toxins in the SoPD project, we consider the biochemical mechanisms by which the external effect of toxins leads to an increase in reactive oxygen species (ROS) or in nitric oxide compounds (see Figure). These species react with α-synuclein to produce damaged proteins that increase the load on the protein disposal facilities and thus increases the risk of accumulating Lewy bodies. The SoPD project aims at developing an integrative modelling approach in order to consider not only the α-synuclein aggregation problem, but also the underlying cellular response to oxidative and energy stressing. This will be done by including the effect of toxins on energy metabolism, mitochondria, oxidative stress pathways and will be necessary in order to elucidate the role of toxins on PD development.

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Contact point

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Selected References

J. W. Langston, P. Ballard, J.W. Tetrud, and I. Irwin. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219:979-980, 1983. doi: 10.1126/science.6823561.

O. von Bohlen und Halbach, A. Schobera, and K. Krieglstein. Genes, proteins, and neurotoxins involved in Parkinsons Disease. Progress in Neurobiology., 73(3):151-177, 2004. doi:10.1016/j.pneurobio.2004.05.002.

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.

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.

A. Raichur, S. Vali, F. Gorin Dynamic Modelling of α-synuclein Aggregation for the Sporadic and Genetic forms of Parkinson’s Disease. Neuroscience, 142:859-870, 2006. doi:10.1016/j.neuroscience.2006.06.052.

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