The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration

Abstract

Damage to DNA is generally considered to be a harmful process associated with aging and aging-related disorders such as neurodegenerative diseases that involve the selective death of specific groups of neurons. However, recent studies have provided evidence that DNA damage and its subsequent repair are important processes in the physiology and normal function of neurons. Neurons are unique cells that form new neural connections throughout life by growth and re-organisation in response to various stimuli. This "plasticity" is essential for cognitive processes such as learning and memory as well as brain development, sensorial training, and recovery from brain lesions. Interestingly, recent evidence has suggested that the formation of double strand breaks (DSBs) in DNA, the most toxic form of damage, is a physiological process that modifies gene expression during normal brain activity. Together with subsequent DNA repair, this is thought to underlie neural plasticity and thus control neuronal function. Interestingly, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease, manifest by a decline in cognitive functions, which are governed by plasticity. This suggests that DNA damage and DNA repair processes that normally function in neural plasticity may contribute to neurodegeneration. In this review, we summarize current understanding about the relationship between DNA damage and neural plasticity in physiological conditions, as well as in the pathophysiology of neurodegenerative diseases.

Keywords: DNA damage; DNA repair; neural plasticity; neurodegeneration; synaptic plasticity.

Figure 1

Simplified model of the interplay between neural plasticity and DNA damage and repair. Activation of NMDA/AMPA receptors at synapses induces SSBs or DSBs and promotes their repair by BER or NHEJ, respectively. In turn, DNA damage and repair alters the expression and activity of these receptors, which modulates neuronal gene expression, leading to changes in plasticity.