Overexpression of the X-Linked Inhibitor of Apoptosis Protein (XIAP) in Neurons Improves Cell Survival and the Functional Outcome after Traumatic Spinal Cord Injury

Abstract

Mechanical trauma to the spinal cord causes extensive neuronal death, contributing to the loss of sensory-motor and autonomic functions below the injury location. Apoptosis affects neurons after spinal cord injury (SCI) and is associated with increased caspase activity. Cleavage of X-linked inhibitor of apoptosis protein (XIAP) after SCI may contribute to this rise in caspase activity. Accordingly, we have shown that the elevation of XIAP resulted in increased neuronal survival after SCI and improved functional recovery. Therefore, we hypothesise that neuronal overexpression of XIAP can be neuroprotective after SCI with improved functional recovery. In line with this, studies of a transgenic mice with overexpression of XIAP in neurons revealed that higher levels of XIAP after spinal cord trauma favours neuronal survival, tissue preservation, and motor recovery after the spinal cord trauma. Using human SH-SY5Y cells overexpressing XIAP, we further showed that XIAP reduced caspase activity and apoptotic cell death after pro-apoptotic stimuli. In conclusion, this study shows that the levels of XIAP expression are an important factor for the outcome of spinal cord trauma and identifies XIAP as an important therapeutic target for alleviating the deleterious effects of SCI.

Reanalysis of published histological data can help to characterize neuronal death after Spinal Cord Injury

“…This contrasts with our current findings where neurons are nearly absent at this distance. These disparities could suggest that caudal preservation is more constrained than rostral preservation, a possibility supported by our results in Reigada et al . (2023) but not in the data that underpins the present study (Reigada et al ., 2015).…”

“…This effect gradually wanes, ultimately resulting in less than 50% neuronal loss at a distance of 1.2 mm. We observed a similar pattern of neuronal loss within 400 microns caudal to the injury epicenter, with subsequent progressive survival as the distance from the epicenter increased in a recent investigation, examining neuronal survival following SCI in both wild-type (WT) and XIAP overexpressing C57BL/6 mice (Reigada et al ., 2023). In a similar contusive model with higher severity (75 vs 50 Kdynes), Sauerbeck et al .…”

“…On the contrary, dealing with biological variability will benefit from increasing the sample and incorporating additional information on the injury. Our intention for future analyses is to incorporate samples from additional studies carried out by the group (Muñoz de Galdeano et al ., 2018; Reigada et al , 2023) as well as to additional sources of information ( eg . tissue sparing) so we can characterize the variability of neuronal death through individuals and studies.…”