The Involvement of DNA Damage and DNA Repair in the Pathophysiology of Spinal Cord Injury

Abstract

Spinal cord injury is a devastating condition that affects about 21 million people worldwide, leading to severe disabilities. These injuries impact motor functions, sensory perception, autonomic processes, psychological well-being, and social interactions, significantly burdening patients, their families, and healthcare systems. Unfortunately, despite extensive research, there is no cure for spinal cord injury yet. This PhD Thesis focuses on how oxidative stress following spinal cord injury causes DNA damage, how the body's DNA repair mechanisms influence recovery, and how we therapeutically can influence DNA repair to improve recovery after a spinal cord injury. When the spinal cord gets injured, DNA damage happens almost immediately at the injury site. In a study with mice, I saw DNA damage around the injury within one hour after the injury. Over time, this damage spread to surrounding spinal cord areas. DNA damage appeared slightly later in nerve cells (neurons), peaking around one day after the injury. This damage is followed by early cell death and later by a process called apoptosis, where cells self-destruct in a controlled way. Thus, DNA damage might be causing additional death of neurons after spinal cord injury. During evolution, humans acquired several DNA repair mechanisms to correct different DNA damage types. Data analyses revealed that after a spinal cord injury, there is an upregulation of genes responsible for repairing DNA damage. This increased DNA repair presence is seen from one day after the injury, peaks three days post-injury, and stays high for up to 28 days. Two main types of DNA repair pathways respond to spinal cord injury: 1) Repair mechanisms used during cell division, which involves cells like glial and immune cells that are dividing to help repair the injury; and 2) Repair systems for oxidative DNA damage that likely work to help neurons survive damage caused by oxidative stress. Having knowledge about DNA repair systems helps in revealing new therapeutic approaches. To further study DNA repair responses, a lab model was developed using injured motor neuron cells that were monitored by live imaging to track cell death. By blocking specific DNA repair pathways using small molecule inhibitors, I found that stopping key repair processes increased neuron death, indicating that these pathways are essential for neuron survival after injury. Additionally, more advanced models were developed that can be used in future studies to validate these initial observations. DNA repair requires a lot of energy from the cell in the form of NAD+. Two potential treatments targeting DNA repair responses to improve cell survival after spinal cord injury were tested: nicotinamide riboside to boost cellular NAD+ levels, and PARP inhibitors to manage DNA repair activity. Although previous studies showed promise, neither of these treatments significantly improved the recovery of injured mice. Further analysis is needed to understand why these treatments have experienced mixed success in different studies. This research bridges the fields of spinal cord injury and genome integrity, showing that DNA damage is increased following spinal cord injury and that DNA repair mechanisms contribute not only to brain health but likely to recovery after spinal cord injury. Understanding how DNA damage and DNA repair work after a spinal cord injury is crucial in developing new treatments that can help patients.