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10 - Neurodegenerative disease and the repair of oxidatively damaged DNA

from Part I - Basic aspects of neurodegeneration

Published online by Cambridge University Press:  04 August 2010

M. Flint Beal ,
Anthony E. Lang  and
Albert C. Ludolph
By
Marcus S. Cooke
M. Flint Beal
Affiliation:
Cornell University, New York
Anthony E. Lang
Affiliation:
University of Toronto
Albert C. Ludolph
Affiliation:
Universität Ulm, Germany
Marcus S. Cooke
Affiliation:
Departments of Cancer Studies and Genetics, University of Leicester, Leicester Royal Infirmary, UK
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Summary

Free radicals and oxidative damage to DNA

In addition to endogenous sources of free radicals, such as those derived from normal metabolism (see Chapter 1), pathophysiological or environmental events may also generate free radicals. Cellular biomolecules, including nucleic acids, proteins and lipids are all targets for these damaging species. Reactive oxygen species (ROS) are of particular interest. Enzymic and non-enzymic antioxidants (discussed in Chapter 2) contribute to the limit on the extent to which ROS are produced, and hence their interaction with cellular components. If the balance between the anti- and pro-oxidant factors is altered in favour of the latter, a condition of oxidative stress arises, with a concomitant increase in biomolecule modification. Given its central role in cellular events, modification of DNA, for example 8-hydroxyguanine (8-OH-Gua), and thymine glycol (Tg), has been the subject of intense study. Such lesions may have a plethora of effects, most notably mutation, but also replicative block, deletions, microsatellite instability and loss of heterozygosity, as well as various epigenetic effects (for review see Cooke et al., 2003). Furthermore, a great deal of literature exists that describes elevated levels of lesions in a variety of diseases, suggesting that the induction of damage is an important event in pathogenesis (for review, see Cooke et al., 2003). Unlike oxidatively modified lipids and proteins, which may be removed and replaced as part of normal turnover, DNA needs to be repaired, and intense study has revealed much about the processes that maintain genome integrity.

Type
Chapter
Information
Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
 , pp. 131 - 140
Publisher: Cambridge University Press
Print publication year: 2005

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