Mechanisms of Disease: DNA Repair Defects and Neurological Disease

Kalluri Subba Rao


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

In This Article

Summary and Introduction


In this Review, familial and sporadic neurological disorders reported to have an etiological link with DNA repair defects are discussed, with special emphasis placed on the molecular link between the disease phenotype and the precise DNA repair defect. Of the 15 neurological disorders listed, some of which have symptoms of progeria, six—spinocerebellar ataxia with axonal neuropathy-1, Huntington's disease, Alzheimer's disease, Parkinson's disease, Down syndrome and amyotrophic lateral sclerosis—seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this induces. Five of the conditions (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down syndrome, and triple-A syndrome) display a defect in the nucleotide excision repair pathway, four (Huntington's disease, various spinocerebellar ataxias, Friedreich's ataxia and myotonic dystrophy types 1 and 2) exhibit an unusual expansion of repeat sequences in DNA, and four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) exhibit defects in genes involved in repairing double-strand breaks. The current overall picture indicates that oxidative stress is a major causative factor in genomic instability in the brain, and that the nature of the resulting neurological phenotype depends on the pathway through which the instability is normally repaired.


Efficient DNA repair mechanisms have evolved to ensure the faithful transfer of the genetic make-up to each new generation. Biological evolution is, however, marked by compelling mutations that escape the watchful DNA repair process. In this cyclic process, the genetic apparatus responsible for DNA damage recognition and repair can itself sustain irreversible mutations that are transmitted to the next generation. This process results in offspring with an inherited defect in DNA repair, which, depending on the genetic characteristics of the transmission, will either be expressed as a disease phenotype or remain dormant. In line with the rising complexity of the higher organisms, both the ways in which genomic DNA can be mutated and the number of pathways through which damage can be repaired have increased enormously through evolution.

For a long time the brain was a neglected organ in terms of studies on DNA transactions. Such neglect was not because the brain was considered unimportant, but—primarily—because the postmitotic nature of adult brain cells results in low levels of DNA synthesis and repair. Over the past two decades, however, our ever-increasing knowledge of neurological disorders and the striking susceptibility of the brain to oxidative DNA damage have resulted in considerable attention being focused on improving our understanding of the brain's DNA repair pathways and genomic stability.

The purpose of this article is to review the current state of knowledge regarding neurological diseases that have been found to be linked to a mutation in a crucial component of a DNA repair pathway. It will focus on the relationship between a given neurological disorder and the type of DNA repair pathway that is compromised, with special emphasis given to oxidative DNA damage and its repair. It will also highlight the fact that some DNA-repair-linked disorders show a mixed phenotype, including neurological symptoms, cancer disposition and accelerated aging, underlining the fundamental importance of the DNA repair machinery in health and disease.


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