Mechanisms of Disease: DNA Repair Defects and Neurological Disease

Kalluri Subba Rao

Disclosures

Nat Clin Pract Neurol. 2007;3(3):162-172. 

In This Article

Conclusion and Perspectives

All genetically transmitted disorders or syndromes are essentially caused by a mutation that has been sustained because of a lack of DNA repair, which has then been transmitted to the next generation. What happens if the mutation is in that part of the genomic DNA involved in DNA repair? The consequences would be highly deleterious in the offspring. A number of neurological disorders, as discussed in this Review, seem to have an etiological connection to defects in one or more DNA repair pathways. What is interesting is the fact that even repair defects that have no immediate relevance to the brain genome (for example, an inability to repair ultraviolet-induced DNA damage) will eventually cause neurological abnormalities. In those diseases that are primarily neurological in nature (whether familial or sporadic), however, the vulnerability for defective DNA repair can be expected to appear in the CNS. In this regard, the most important culprit for causing DNA damage in the brain seems to be oxidative stress, and the most important DNA repair pathway to deal with such damage in the brain is BER. This is not to say that the mutations responsible for these disorders are always located in the genes involved in BER, but they do seem to constitute a high proportion. The ubiquitous BER, therefore, seems to be emerging as a guardian against the body's internal forces that cause DNA damage in the brain and possibly in the rest of the body, and should as a consequence become a main therapeutic target. This is the rich dividend of information with which research on neurological diseases has provided us.

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