New step in DNA damage response in neurons discovered

January 18, 2009

Researchers have identified a biochemical switch required for nerve cells to respond to DNA damage. The finding, scheduled for advance online publication in Nature Cell Biology, illuminates a connection between proteins involved in neurodegenerative disease and in cells' response to DNA damage.

Most children with the inherited disease ataxia telangiectasia are wheelchair-bound by age 10 because of neurological problems. Patients also have weakened immune systems and more frequent leukemias, and are more sensitive to radiation.

The underlying problem comes from mutations in the ATM (ataxia telangiectasia mutated) gene, which encodes an enzyme that controls cells' response to and repair of DNA damage.

ATM can be turned on experimentally by treating cells with chemicals that damage DNA. After other proteins in the cell detected broken DNA needing repair, scientists had thought that the ATM protein could activate itself directly. Emory researchers have shown that an additional step is necessary first.

"In neurons that are not dividing anymore, we now know that another regulator is involved: Cdk5," says Zixu Mao, MD, PhD, associate professor of pharmacology and neurology at Emory University School of Medicine.

Working with postdoctoral fellows Bo Tian, PhD and Qian Yang, PhD, Mao found that the Cdk5 protein must activate ATM before ATM can do its job in neurons.

The results support the idea that Cdk5 may be a potential drug target. Cdk5 contributes to normal brain development, and aberrant Cdk5 activity is known to be involved in the death of neurons in several neurodegenerative diseases, including Alzheimer's, Parkinson's and amyotrophic lateral sclerosis.

"Cdk5 has a complex character," Mao says. "It can be bad for neurons if its activity is either too high or too low."

Mao says he and his colleagues were intrigued by reports that in these diseases, neurons that had stopped dividing appear to restart that process, copying their DNA, before dying.

"That's what really kicked us into high gear," he says.

The same process, called "mitotic catastrophe," occurs when neurons suffer DNA damage. Inhibiting either Cdk5 or ATM can reduce the number of neurons that suffer mitotic catastrophe after DNA damage, the authors found.


Tian, B., Yang, Q. and Mao, Z. Phosphorylation of ATM by CDk5 mediates DNA damage signaling and regulates neuronal death. Nature Cell Biology, advance online publication.

Source: Emory University

Explore further: Caloric restriction can be beneficial to the brain, study shows

Related Stories

Impaired recycling of mitochondria in autism?

October 18, 2016

Tuberous sclerosis complex (TSC), a genetic disorder that causes autism in about half of those affected, could stem from a defect in a basic system cells use to recycle their mitochondria, report scientists at Boston Children's ...

Scientists uncover new facets of Zika-related birth defects

October 17, 2016

In a study that could one day help eliminate the tragic birth defects caused by Zika virus, scientists from the Florida campus of The Scripps Research Institute (TSRI) have elucidated how the virus attacks the brains of newborns, ...

Recommended for you

Team finds Southern East Africa getting wetter, not dryer

October 21, 2016

The prevailing notion that the African continent has been getting progressively drier over time is being challenged by a new study that finds that drought has actually decreased over the past 1.3 million years and that the ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.