New step in DNA damage response in neurons discovered

Jan 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.

Reference:

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: Thousands worldwide march against Monsanto and GM crops

Related Stories

Chameleon proteins make individual cells visible

May 19, 2015

Researchers discovered a new mechanism of how fluorescent proteins can change colour. It enables the microscopic visualization of individual cells in their three-dimensional environment in living organisms.

A tale of two roads into protein unfolding

May 11, 2015

You are taking a class on origami and Mr. Otaki asks you to fold that little red piece of paper into a very elaborate design. You have to do it in a very short time. You try your best but you fail. Your origami ...

Recommended for you

Researchers combat bias in next-generation DNA sequencing

56 minutes ago

Ever since scientists completed mapping the entire human genome in 2003, the field of DNA sequencing has seen an influx of new methods and technologies designed to help scientists in their search for genetic ...

11 new species come to light in Madagascar

5 hours ago

Madagascar is home to extraordinary biodiversity, but in the past few decades, the island's forests and associated biodiversity have been under greater attack than ever. Rapid deforestation is affecting the ...

Birds 'weigh' peanuts and choose heavier ones

May 23, 2015

Many animals feed on seeds, acorns or nuts. The common feature of these are that they have shells and there is no direct way to know what's inside. How do the animals know how much and what quality of food ...

User comments : 0

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.