New step in DNA damage response in neurons discovered

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New step in DNA damage response in neurons discovered

http://www.eurekalert.org/pub_releases/2009-01/eu-nsi011609.php

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.