The idea goes that myelin is decorated on its surface with many molecules and when growing axons come into contact with myelin, these molecules “dock” with specific receptors on the growing axon triggering a cascade of signals within the neuron telling it to go no further or even retract. Interfering with this inhibitory interaction is fundamental to a number of experimental treatments that are at various stages of development.
Crucially, there is another known potent inhibitor of axon grow, namely CSPGs [see earlier posts] which increases in concentration at the Glial scar and elsewhere after injury. Exactly how CSPGs repulse axons is poorly understood, however, creating a bit of a black box on the mechanism and thus making it difficult to develop drugs to overcome this inhibition. That is until now, perhaps.
This week, in what may be a very significant paper published in the journal Science, neuroscientists from Harvard Medical School, Boston and Case Western Reserve University, Ohio, appear to have identified a protein on the surface of the growing axon which has all the hallmarks of a receptor for CSPGs and therefore potentially important in the cause of regenerative failure.
In the paper Shen et al., develop their case thus;
(i) a protein PTPsigma (a member of a large family of transmembrane protein tyrosine phosphatases; PTPs) was known to bind other proteoglycans important in early development so it might also bind to CSPGs which structurally similar
(ii) they found that PTPsigma did indeed bind to CSPGs
(iii) they demonstrated that binding was a genuine biological interaction because binding sites could be saturated and the interaction was high-affinity – ie. it was not a non-specific interaction
(iv) pre-treatment with chondroitinase (cleaves side chains on CSPGs) renders CSPGs inactive as inhibitors and also abolishes much of the binding with PTPsigma – indicating the side chains are important to this receptor binding as they are also in inhibition
In cell culture, they found that PTPsigma bound to cells responsible for producing the Glial scar – astrocytes.
So they had very strong evidence that PTPsigma binds to CSPGs. That in itself was not enough, so they next tested the theory that PTPsigma was functionally important to the failure of axons to grow. To do this they needed a mouse strain that did not posses a functional PTPsigma arguing that neurons cultured from such a mouse would grow better over CSPGs, which they did.
Their findings open the door on a potential new and exciting lead for drug design and treatment of SCI and other neural injury/diseases.
Notes:
CSPGs = chondroitin sulphate proteoglycans
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