DNA Damage is a Part of Neural Plasticity, Complicating the Study of Its Relevance to Aging in the Brain
As noted by the authors of today's open access paper, there is ample evidence to show that double strand breaks in DNA occur during the normal activity of neurons, such as during the synaptic remodeling necessary to learning and memory. Evolution loves reuse, and few possibilities are ignored! This process of utilitarian double strand breaks appears to be used to ensure that nuclear DNA is spatially reconfigured in such a way as to ensure that certain genes are expressed for a time; recall that the pattern of gene expression at any given moment is very much a function of how the mass of nuclear DNA is packaged, which parts of it, and hence which gene sequences, are accessible at any given time to the machinery of transcription.
This is all very interesting, as stochastic DNA damage, such as double strand breaks, is thought to have a role in degenerative aging. But if the process is taking place on a regular basis during the normal function of neurons, that makes it harder to study in the context of aging and neurodegeneration. On the one hand, DNA damage can spread through tissues from stem cells, and this happens in the brain even given the long-lived nature of neurons. On the other hand, recent research has suggested that the process of repairing repeated double strand breaks can produce some of the epigenetic change of aging as a side-effect, due to depletion of molecules needed to maintain a youthful configuration of nuclear DNA. More research is needed to fill out this presently sparse sketch; important details are missing, and the present understanding of DNA damage in the brain is incomplete.
The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration
DNA damage is now widely implicated in aging and the pathophysiology of age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). However, emerging evidence suggests that DNA damage and DNA repair are not only induced by pathological conditions. The same processes involved in neurodegeneration as we age are also involved in fundamental physiological functions of neurons that are related to neural plasticity. Hence, DNA damage and repair are associated with neural plasticity, implying an important role for these processes in neuronal function. Furthermore, in neurodegenerative diseases the selective death of specific groups of neurons is present. This suggests that the unique properties of neurons may contribute to selective neurodegeneration in pathophysiology.
Several studies have shown that neuronal activity generates double strand breaks (DSBs) in cultured neurons. A recent study concluded that DSBs are generated physiologically to resolve topological limitations to gene expression in neurons. Topoisomerase enzymes participate in the overwinding or underwinding of DNA and thus they manage DNA topological constraints. Neuronal activity produces DSBs at specific loci in vitro by topoisomerase IIβ (TopIIβ), in the promoters of early response genes (ERGs, also called immediate early genes, IEGs) that are crucial for experience-driven changes to synapses, learning, and memory. Interestingly, the expression patterns of ERGs in response to neuronal stimulation correlated well with the formation and repair of activity-induced DSBs, implying that generation of DSBs and their subsequent repair are essential steps for proper gene function. Furthermore, DSBs produced during neuronal excitation were repaired within 2 hours of the initial stimulus, suggesting that this process employs rapid DNA repair mechanisms such as non-homologous end joining (NHEJ).
Dysfunction in these processes of DNA damage and repair is also related to a decline in cognitive function and neuronal death in neurodegenerative diseases. However, human post-mortem tissues represent the end-point stage of the disease. Hence studies examining these tissues cannot be used to determine whether DNA damage has a primary or secondary role in pathogenesis. Future studies on the relationship between plasticity and DNA damage may provide a better understanding of the cellular processes that contribute to higher order brain functions.
Distinct groups of neurons are affected in different neurodegenerative diseases, such as motor neurons in ALS or neurons of the entorhinal cortex in AD, and these cells are specialized to perform specific functions. Given that DNA damage and repair are important for the unique functions of neurons, which in turn depend on their activation, it is possible that the interplay between DNA damage and neural plasticity is unique for specific groups of neurons. This could operate through the activation of specific genes by DNA damage, which would differ depending on the type of neurons involved and their associated functions. Therefore, a better understanding of the interplay between DNA damage and neural plasticity is required, as well as dysfunction in these processes in disease. In particular, the inclusion of specific neuronal types may reveal the causes of selective neuronal death in distinct neurodegenerative diseases.
To date, no previous studies have examined therapeutic strategies directed at DNA damage and repair in relation to aberrant neural plasticity. However, this approach has the potential to identify novel treatments for impaired cognitive functions in neurodegenerative diseases associated with excessive DNA damage.