From extending lifespan to bolstering the immune system, the drug’s effects are only just beginning to be understood.
Researchers find that temporary double-stranded DNA breaks commonly result from normal neuron activation—but expression of an Alzheimer’s-linked protein increases the damage.
March 24, 2013|
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 and the University of California, San Francisco, hit upon the arresting notion that severing and repairing DNA is “part and parcel” of normal brain activity in the course of his research on changes in genome stability in Alzheimer’s disease (AD), which is characterized by tangled clumps of amyloid ß proteins and damaged neuronal DNA. Hoping to learn more about DNA damage associated with high amyloid levels in the brain, Mucke’s team chose to focus on double-stranded DNA breaks, which neuroscientists generally consider the most severe form of damage.
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.
March 25, 2013
Has anybody considered the impact of stress? I'm not a scientist but maybe an evrinomental change triggers posibility of change in dna, but done in a radical way it also increases stress, whitch is one of most destructive factors for our bodies?
We have made a quite stressful society and evrinoment to live in. And as I seen in many cases - negative emotions and stress block acces to some memories, and memory overall (works the same way as we are forgetting bad things from our past -> if our brain percives our past as stressful, so it tries to "clean up" from it) and then -> Mechanism of forgetting runnig for a long time builds a "habit" for brain, combined with dna changes without possibility (or "thinking space") to get around, leads to an increasing mess..
Hope it doesn,t sound too stupid, and sorry if I made any mistakes in english, have a good day! :)
March 25, 2013
I find this article very interesting and fascinating. My Co-Authors and I can corroborate its conclusions in vivo, i.e., in humans. In addition, interestingly, we have demonstrated that, regarding, e.g., AD., there is an Inherited Real Risk of such a disorder, a flurry of environmental risk factors may act on, bringing about both mit-DNA and n-DNA specific breaking:
Marco Marchionni, Simone Caramel, Sergio Stagnaro. Inherited Real Risk of Alzheimer’s Disease: bedside diagnosis and primary prevention.Frontiers in Neuroscience, in http://www.frontiersin.org/Aging_Neuroscience/10.3389/fnagi.2013.00013/full CmdV
March 25, 2013
Wait. For awhile, we've been told to keep our minds active to stave off Alzheimer's Disease, and now we are told excessive brain activity in the presence of AD genes could be harmful! This report literally turns research on it's head...
March 26, 2013
There may be stress-induced double strand breaks in neuronal DNA.But the question is: is this temporary or lasting or permanent? Does this break lead to realingnment of genes or their inactivation?
March 27, 2013
One hopes they'll whole genome sequence several single nuclei from the memory region, ideally in human. Nerve cells know how to handle electrical currents, dsDNA is an electrical conductor with properties strongly dependent on local conditions inc DNA sequence. "Makes sense" that terminally differentiated neurons might find an alternative use for the information holding capacity of DNA to store memories. It would read out with the speed of light in DNA which is consistent with what we know about memory recall. Means there must be an electrical connection between the nerve cell membrane structures and the nucleus. Interesting to know if any transmission EM people have seen structures they can't explain in memory nerve cells.