After a spinal cord contusion injury, rats recover more motor function when treated with an enzyme that removes terminal sialic acids from complex gangliosides
Axons in the central nervous system (CNS) are prevented from regenerating after injury, partly due to axon regeneration inhibitors (ARIs) that accumulate at injury sites. Binding of these molecules, which include Siglec-4 (myelin-associated glycoprotein, MAG), to complementary receptors on axons results in outgrowth arrest. In a pre-clinical study, Ronald Schnaar and colleagues show that targeting the interaction of MAG with gangliosides GD1a and GT1b might provide effective therapy for spinal injuries. They report in Proceedings of the National Academy of Sciences of the USA that treatment with recombinant Vibrio cholerae sialidase, which cleaves terminal sialic acids from complex gangliosides, significantly improved recovery in rats with spinal injury.
Targeting ARIs is a promising area of spinal injury research, and sialidase treatment is known to stimulate outgrowth of CNS axons into peripheral nerve grafts. To test whether sialidase can overcome the usual inhibitory environment for axon regeneration after spinal injury, the authors used a rat model of the most common type of spinal cord injury seen in humans. Sialidase or control was delivered immediately after injury, and continuously for two weeks, and hindlimb function was evaluated using a locomotor rating scale. Staining of spinal cord sections with highly specific monoclonal antibodies to gangliosides showed that the sialidase penetrated the spine and depleted GT1b. Correspondingly, staining of GM1, the monosialoganglioside product of V. cholerae sialidase activity, was increased. GM1 does not bind MAG.
For two weeks after injury, partial recovery of hindlimb function occurred equally in the control and sialidase-treated rats, reaching an average score of 11 on the locomotor scale. However, as restorative processes had time to develop, the scores of the two groups diverged. After 5 weeks, the sialidase-treated rats reached a score of 15.6 on average, compared with 12.6 for the controls. Functionally, this represented one half of the sialidase treated rats attaining consistent coordination and frequent toe clearance, as opposed to fewer than 10% of control rats.
Sialoglycans mediate inflammation, which causes secondary tissue damage that exacerbates the initial trauma. Sialidase treatment however did not reduce lesion size or protect white or gray matter, showing that recovery is improved without any reduction in damage. Instead, the density of serotonergic axons caudal to the injury site was increased in sialidase-treated animals, consistent with the conclusion that the treatment enhances regeneration, sparing or sprouting of axons.
The sialidase used in this study is easily produced and purified, and has good stability. Improved locomotion after sialidase treatment is consistent with the conversion of MAG-binding gangliosides to GM1, but it does not exclude the possibility that other sialic acid linkages could be involved as the enzyme has broad specificity. Either way, this study shows that delivering sialidase to contused spinal cord is feasible, and might be of significant therapeutic benefit.
Related articles
von Elstermann, M. (2009) Tissue development: Cleaving an acidic sugar promotes differentiation
von Elstermann, M. (2007) Neuronal injury: Putting the brake on axonal outgrowth
Original research paper
- Mountney, A. et al. Sialidase enhances recovery from spinal cord contusion injury. Proc. Natl Acad. Sci. USA(published online 7 June 2010) doi:10.1073/pnas.1006683107 | Article
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