Abstract
Spinal cord injury (SCI) is a devastating condition that leads to permanent disability because injured axons do not regenerate across the trauma zone to reconnect to their targets. A prerequisite for axonal regeneration will be the prevention of retrograde degeneration that could lead to neuronal death. However, the specific molecular mechanisms of axotomy-induced degeneration of spinal-projecting neurons have not been elucidated yet. In lampreys, SCI induces the apoptotic death of identifiable descending neurons that are “bad regenerators/poor survivors” after SCI. Here, we investigated the apoptotic process activated in identifiable descending neurons of lampreys after SCI. For this, we studied caspase activation by using fluorochrome-labeled inhibitors of caspases, the degeneration of spinal-projecting neurons using Fluro-Jade C staining, and the involvement of the intrinsic apoptotic pathway by means of cytochrome c and Vα double immunofluorescence. Our results provide evidence that, after SCI, bad-regenerating spinal cord-projecting neurons slowly degenerate and that the extrinsic pathway of apoptosis is involved in this process. Experiments using the microtubule stabilizer Taxol showed that caspase-8 signaling is retrogradely transported by microtubules from the site of axotomy to the neuronal soma. Preventing the activation of this process could be an important therapeutic approach after SCI in mammals.
Highlights
In humans, as in the other mammals, spinal cord injury (SCI) causes permanent disability
Previous studies revealed that bad regenerator/poor survivor neurons show high levels of activated caspases in the first 2 weeks following a complete SC transection as revealed by fluorochrome-labeled inhibitors of caspases (FLICA) labeling [30,31,32] and that intense FLICA labeling and TUNEL staining are observed in bad regenerators several weeks after a complete SC transection [32]
Our results suggest that the centripetal activation of caspases depends on microtubule-based retrograde transport of stress signals
Summary
As in the other mammals, spinal cord injury (SCI) causes permanent disability. There is still some controversy whether spinal cord (SC) projecting neurons of the brain of mammals die after SCI. In two recent studies using rats, no evidence was found for the death of corticospinal neurons after SCI [14] and suggested that these neurons suffer atrophy after SCI but do not die [15]. The death or degeneration (atrophy) of descending neurons following SCI seems to involve an apoptotic process. This is suggested by the appearance of TUNEL staining and activated caspase-3 immunoreactivity in descending neurons of the brain (pontine reticular neurons [10]; corticospinal neurons [9, 11]).
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