Consequences Of Redox Imbalance

OS damage compromises all biomacromolecules - polynucleotides, proteins, sugars and lipids, leading to a critical failure of biological functions and finally, cell death. Because of their high reactivity, free radicals cannot be measured directly. However, there are a number of indices for OS in the SN of PD patients. Their localization and primary targets depend on the sites of their formation:

• Lipid peroxidation of membranes that are crucial for cell viability, occurs as a consequence of direct reaction of fatty acids of polar lipids with oxygen or a reaction catalyzed either by metals like iron or by NADPH cytochrome P-450 reductase. It leads to the formation of free radical intermediates and semistable peroxide. Increased levels of secondary products like conjugated dienes, hydrocarbon gases (e.g. ethane) and carbonyl compounds (e.g. malondialdehyde) and decreased levels of polyunsaturated fatty acid have been demonstrated (90-125).

• Oxidation of proteins may occur directly as protein side chains are oxidized leading to a loss of function of proteins and a deactivation of enzymes (126,127). Often, thiols of proteins involved in the regulation of enzyme activity are directly oxidized. Increase of malondialdehyde has been suggested to lead to intra- and inter-molecular cross-links of proteins (43). Conformational changes leading to an increase in hydrophobicity may result in aggregation or precipitation of proteins, which can no longer be subjected to the normal protein degradation pathway. Additionally, oxidative damage of proteins may occur by the adduction of secondary products like oxidation of sugar i.e. glycoxidation, or of polyunsaturated lipids, i.e. lipoxidation (128,129).

• DNA and RNA damage are major consequences of OS. Exposure of nucleic acids to reactive species may result in strand breakage, nucleic acid-protein cross-linking and nucleic base modification. Base modification, cross-linking of DNA-DNA and DNA-proteins, sister chromatid exchange and single- or double-strand breaking may lead to disruption of transcription, translation and DNA replication. Increased levels of 8-hydroxy-2'hydroxyguanine and thymidine glycol indicating DNA base damage have been demonstrated in the SN and striatum of PD brain (130,131). Mitochondrial DNA (mtDNA), which is transiently attached to the inner mitochondrial membrane where a large amount of ROS is produced, is particularly vulnerable to oxidative damage (43). Moreover, DNA repair mechanisms in the mitochondria are less efficient than in the nucleus. Therefore, ROS-mediated mtDNA damages may contribute to mitochon-drial dysfunction generated by endogenous reactive intermediates which act directly on mitochondrial proteins (132). RNA oxidation has also been observed in neurons of PD patients (133).

• ROS interfere with signal transduction and gene expression affecting cell death. Within neurons, the intracellular pathways of signaling and gene expression affecting cell survival are especially vulnerable to redox changes. Complex interactions of various sites of signal transduction with radicals via modification of enzymes leading to altered signal transduction and eventually altered gene expression have been described (43). These include increased formation of GSSG resulting in the inactivation of protein phosphatases, which again negatively regulate protein kinases leading to increases in apoptosis and expression of inflammatory genes. On the other hand, ROS can effectively delay activation of caspases and calpains which are important executors of apoptosis. Therefore, a balanced redox equilibrium is important to maintain the pathways important for cell survival in neurons.

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