Scientists at Emory University School of Medicine have announced the identification of a biochemical switch, which is required for nerve cells to respond to DNA damage.
The researchers say that their finding illuminates a connection between proteins involved in neurodegenerative disease and in cells' response to DNA damage.
Most children who inherit the disease ataxia telangiectasia are rendered wheelchair-bound by the time they turn 10, because of neurological problems. Patients also have weakened immune systems and more frequent leukemias, and are more sensitive to radiation.
According to the researchers, the problem mainly results from mutations in the ATM (ataxia telangiectasia mutated) gene, which encodes an enzyme that controls cells' response to and repair of DNA damage.
The researchers say that it is possible to turn on ATM by treating cells with chemicals that damage DNA. Once other proteins in the cell detect broken DNA needing repair, they say, the ATM protein could activate itself directly.
The team 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," Nature Cell Biology quoted says Dr. Zixu Mao, associate professor of pharmacology and neurology at Emory University School of Medicine, as saying.
Mao and his colleagues have found that the Cdk5 protein must activate ATM before the gene can do its job in neurons.
Based on their findings, the researchers came to the conclusion 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. It can be bad for neurons if its activity is either too high or too low," Mao says.
Mao revealed that his team 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.