Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration

Abstract

Oxidative stress has been identified as an important contributor to neurodegeneration associated with acute CNS injuries and diseases such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic stroke. In this review, we briefly detail the damaging effects of oxidative stress (lipid peroxidation, protein oxidation, etc.) with a particular emphasis on DNA damage. Evidence for DNA damage in acute CNS injuries is presented along with its downstream effects on neuronal viability. In particular, unchecked oxidative DNA damage initiates a series of signaling events (e.g. activation of p53 and PARP-1, cell cycle re-activation) which have been shown to promote neuronal loss following CNS injury. These findings suggest that preventing DNA damage might be an effective way to promote neuronal survival and enhance neurological recovery in these conditions. Finally, we identify the telomere and telomere-associated proteins (e.g. telomerase) as novel therapeutic targets in the treatment of neurodegeneration due to their ability to modulate the neuronal response to both oxidative stress and DNA damage.

Figure 1. Mechanisms linking oxidative stress, DNA damage/repair, and telomere dysfunction in CNS injury

Oxidative stress results in the accumulation of cellular ROS/RNS which in turn leads to DNA damage, lipid peroxidation, and protein oxidation, in neuronal cells. As a result of DNA damage and associated telomere dysfunction, a number of downstream signaling cascades are activated that may determine cellular fate. Induction of appropriate DNA repair systems may reverse oxidative modifications and promote neuronal survival. However, when oxidative DNA damage overwhelms repair systems, cell cycle reentry and p53 may initiate neuronal apoptosis. Neuroprotective agents may act a number of points in the proposed pathway (including ROS/RNS production, telomerase expression/activity, etc.) to prevent neuronal loss in the context of acute neurodegeneration.