Researchers link oxidative stress and neurodegenerative disease
By Robin Arnette
Scientists have known for decades that certain kinds of DNA damage may cause neurodegenerative illnesses in humans, but the exact mechanism for how it worked remained elusive. Now, researchers from NIEHS and Florida International University (FIU) in Miami offer an explanation for how degenerative nerve disorders such as Huntington’s disease arise.
Research from other groups determined that a three nucleotide segment of DNA called trinucleotide repeats (TNRs) are expanded or appear in multiple copies in Huntington’s disease patients, but NIEHS Laboratory of Structural Biology investigator Samuel Wilson, M.D., and former colleague Yuan Liu, Ph.D., (http://casgroup.fiu.edu/chemistry/faculty.php?id=802) went a step further. They demonstrated that expansions in TNRs are linked to cellular oxidative stress or highly reactive oxygen atoms that damage DNA. A summary of the findings was published online in a review article (http://www.ncbi.nlm.nih.gov/pubmed/22285516) on Jan. 27 in Trends in Biochemical Sciences. The report advanced a hypothesis that Wilson, Liu, and their collaborators introduced in two earlier papers (see Liu et al., 2009 (http://www.ncbi.nlm.nih.gov/pubmed/19674974) and Kovtun et al., 2007 (http://www.ncbi.nlm.nih.gov/pubmed/17450122) ).
“We felt that the molecular mechanism for triplet repeat expansion was not spelled out enough in the original articles,” Wilson said. “The review will be more widely read and clarifies how base excision repair could be connected to triplet repeat expansion.”
The birth of TNRs
Wilson explained how the pieces of the puzzle fit together, by providing background on how he believes expansions of TNRs originate. He said cells maintain an environment of positive- and negative-charged ions. When that balance is disturbed, normal cellular processes produce peroxides and free radicals that harm all components of the cell, especially the DNA, by creating small lesions that attach to nucleotides. If the damage isn’t fixed, it could lead to mutations or breaks when the DNA makes copies of itself during replication.
Base excision repair (BER), according to Wilson, corrects the problem by removing this oxidized DNA but, in the process, it creates a strand break that allows the DNA to snap into a hairpin structure. The resulting gap is filled in with extra nucleotides and sealed. During the next round of replication, the additional nucleotides will result in a slightly longer DNA thread. Each subsequent round of copying will lead to multiple copies of the first additional nucleotides, collectively known as TNRs.
Wilson said, “In the pathobiology of DNA expansion, we suggest that this mechanism is one of the early events that initiate a shorter expansion. Longer expansions associated with Huntington’s disease might occur through a different mechanism.”
TNRs are part of disease etiology
In the DNA of a person with Huntington's disease, (http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001775/) according to the Nature Publishing Group website Scitable, (http://www.nature.com/scitable/content/examples-of-genetic-diseases-caused-by-expanding-27926) the sequence CAG is repeated anywhere from 37 to 121 times, but there are many other neurodegenerative diseases that are associated with triplet repeat expansion. For example, in Jacobsen syndrome, (http://ghr.nlm.nih.gov/condition/jacobsen-syndrome) CGG is repeated 100-1000 times, and in myotonic dystrophy, (http://ghr.nlm.nih.gov/condition/myotonic-dystrophy) CTG may appear up to 3000 times.
Wilson said, in addition to the development of TNRs via oxidative stress, children may inherit the propensity to have triplet repeat expansion from their parents. However, these individuals may have a bright future. Wilson and Liu’s work in mouse models demonstrated when the BER enzyme that removes oxidative lesions is eliminated, TNRs fail to occur.
Liu said, “Our study on understanding these mechanisms will help to identify base excision repair as a new target for prevention, diagnosis, and treatment of oxidative stress-induced human neurodegenerative diseases.”
Citation: Liu Y, Wilson SH. (http://www.ncbi.nlm.nih.gov/pubmed/22285516) 2012. DNA base excision repair: a mechanism of trinucleotide repeat expansion. Trends Biochem Sci; doi:10.1016/j.tibs.2011.1 2.002 [Online 27 January 2012].