FLICKR, MIKEBLOGSDouble-stranded breaks in DNA—generally thought to be a severe form of damage—may simply be all in a day’s work for neurons, according to research published today (March 24) in Nature Neuroscience. Scientists studying mice reported that normal neuronal activation stimulated by exposure to new environments can cause temporary DNA breaks—suggesting that transient damage may be involved in learning and memory. Additionally, expressing a protein linked to Alzheimer’s disease exacerbates the damage, but blocking neuron activation can keep DNA breaks at a normal level, hinting at possible therapeutic strategy to prevent cognitive decline.

“It’s breathtaking work,” said Karl Herrup, a neurogeneticist at Rutgers University who was not involved in the research. DNA damage can be very dangerous to neurons, which aren’t readily replaced, so it seems likely that the cells must be getting something “worthwhile” from the breaks, said Herrup.

Neurologist Lennart Mucke at the Gladstone Institutes...

The team turned to a mouse model for AD, the J20 mouse, which expresses the human precursor of amyloid ß (hAPP) at high levels. By 6 months, these mice exhibit deficiencies in learning and memory characteristic of AD. To detect double-stranded DNA breaks, the researchers looked for the gH2A.X variant of a specific histone protein, which is known to cluster at double-stranded breaks.

The researchers exposed J20 and wildtype mice to new cages to increase neuron activity. Surprisingly, after 2 hours in the novel environments, the number of gH2A.X -positive neurons spiked in the brains of both healthy and diseased animals, primarily in areas critical for memory formation and learning—suggesting that the brain activity itself was triggering DNA damage.

Interestingly, the damage was resolved in wildtype mice within 24 hours back in their home cages, but the damage persisted in J20 mice. Furthermore, the damage was higher in J20 mice, which had up to three times as many gH2A.X-positive neurons—and the differences could be detected as early as 1 month, before the J20 mice began exhibiting cognitive symptoms. The results suggest that perhaps the high levels of amyloid in the brains of these mice was preventing DNA repair.

Mucke’s team tested whether reducing brain activity in J20 mice alleviated their double-stranded breaks, and found that J20 mice treated with an anti-epileptic drug for 1 month had normal levels of DNA damage.

It’s not yet clear what function, if any, these DNA breaks serve, acknowledged Mucke, whose lab is currently focusing on this question. Given that neuronal activation leads to changes in gene expression that enable animals to learn and form memories, it’s possible that the double-stranded DNA breaks enable these changes in some way.  If so, “the challenge is how to integrate this into our way of thinking about not just neurobiology, but gene regulatory processes in general,” said Herrup.

Alternatively, the damage may simply be a side effect of other activation processes. Herrup also cautions that the assay used to confirm the double-stranded breaks may have in fact broken DNA that was simply rendered fragile by neuron activation-induced modifications.

But if the results hold up, Mucke says he sees therapeutic potential in the findings. It may be that “we can protect the neuronal genome inside nerve cells from amyloid damage by preventing abnormal excitatory activity using readily available anti-epileptic drugs,” he speculated.

It’s an attractive strategy, but Mark Mattson, a neuroscientist at the National Institute of Aging who did not participate in the research, cautioned that reducing neuronal activity could have negative consequences. Treating neurons with anti-epileptics been shown to reduce levels of brain-derived neurotrophic factor, which helps induce DNA repair, as well as neurotrophins important for keeping neurons healthy, he noted.

In the meantime, the findings are “just the beginning,” said Mucke. “We’ve raised more question than we’ve answered.”

E. Suberbielle et al., “Physiologic neuron activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-ß,” Nature Neuroscience, doi:10.1038/nn3356, 2013.


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