|Study Links Faulty DNA Repair to Huntington’s
Huntington’s disease, an inherited neurodegenerative disorder
that affects roughly 30,000 Americans, is incurable and fatal.
But a new discovery about how cells repair their DNA points to
a possible way to stop or slow the onset of the disease. The research
was funded by the National Institutes of Health (NIH).
“As so often happens, basic research on a fundamental biological
process — in this case, enzymes involved in DNA repair — leads
to new insights about how diseases arise and new approaches for
treating or preventing them,” said NIH Director Elias A. Zerhouni,
The study was published April 22 as an Advanced Online Publication
in Nature and led by Cynthia T. McMurray, Ph.D., a professor
of pharmacology at the Mayo Clinic in Rochester, Minnesota.
Unlike most inherited diseases, Huntington’s disease symptoms
usually don’t appear until middle age, leading scientists to wonder
what triggers the disease onset and whether it can be halted — or
at least slowed down.
People with the disease have a version of a gene called huntingtin
that carries an extra segment with a particular sequence of repeated
subunits. If the segment is too large, the gene produces a faulty
protein that has a destructive effect in the brain.
“Huntington’s disease is a progressive disease, but nobody knows
exactly why,” said McMurray. “Our work supports the idea that the
disease progresses when the extra segment expands over time in
non-dividing cells such as nerve cells.”
McMurray’s study shows that the inserted segment grows when cells
try to remove oxidative lesions, which are caused by byproducts
of the oxygen we breathe. DNA repair enzymes initially keep oxidative
lesions in check, but over time, increasing numbers of lesions
overwhelm the repair systems. Oxidative lesions also accumulate
in people who do not have Huntington’s disease, but because their
huntingtin gene lacks the extra segment it is not prone to expansion.
While scientists have long suspected that oxidative lesions play
a role in Huntington’s disease, the specific role of the lesions
has remained elusive until now.
“Nobody has connected the dots before,” said McMurray.
To show that the extra segment enlarges with age, the researchers
engineered mice to carry a version of the human huntingtin gene
with an inserted segment — one large enough to cause Huntington’s
disease in humans. After a few months — when the mice had
aged — the scientists analyzed the gene and found that the
segment had expanded. They also observed an increase in oxidative
lesions in the mouse DNA.
To see if the oxidative lesions played a role in expansion of
the extra DNA segment, the researchers next deleted OGG1, a key
enzyme in oxidative lesion repair. Without OGG1, the bulk of the
DNA’s oxidative lesions remained untouched, and the inserted segment
did not grow at all or it grew far less than in mice carrying a
working version of OGG1.
These findings show that while doing its part in removing oxidative
lesions, OGG1 triggers a far more damaging effect — the DNA
expansion associated with Huntington’s disease.
“The effect is much like what might happen if a technician came
to repair a minor defect in your computer but was called away by
a more urgent problem midway through the process. Now your computer
is lying in pieces and you’re unable to use it,” said McMurray.
The study suggests that OGG1 might offer a target for the development
of new Huntington’s disease treatments. McMurray’s team is already
pursuing this path and is screening for small molecules that block
OGG1 function. This work may also be relevant to research on other
diseases, such as Alzheimer’s and Parkinson’s, in which oxidative
lesions are believed to play a role.
The NIH components that contributed to this research are the National
Institute of General Medical Sciences, the National Institute of
Neurological Disorders and Stroke and the National Institute of
Environmental Health Sciences.
To arrange an interview with NIGMS Director Jeremy M. Berg, Ph.D.,
contact the NIGMS Office of Communications and Public Liaison at
NIGMS (http://www.nigms.nih.gov) supports basic biomedical research
that is the foundation for advances in disease diagnosis, treatment,
The National Institute of Neurological Disorders and Stroke is
the nation's primary funder of research on the brain and nervous
system. More information about the NINDS and its mission is available
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supports research to understand the effects of the environment
on human health. For more information on environmental health topics,
please visit http://www.niehs.nih.gov/.
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and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
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