Research: Getting rid of SPAM is not just good for the blog, but may also promote remyelination

EpubPreston M et al. Digestion products of the PH20 hyaluronidase inhibit remyelination. Annal Neurol DOI: 10.1002/ana.23788

OBJECTIVE: Oligodendrocyte progenitor cells (OPCs) recruited to demyelinating lesions often fail to mature into oligodendrocytes (OLs) that remyelinate spared axons. The glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions and has been implicated in the failure of OPC maturation and remyelination. We tested the hypothesis that OPCs in demyelinating lesions express a specific hyaluronidase, and that digestion products of this enzyme inhibit OPC maturation.

METHODS: Mouse OPCs grown in vitro were analyzed for hyaluronidase expression and activity. Gain of function studies were used to define the hyaluronidases that blocked OPC maturation. Mouse and human demyelinating lesions were assessed for hyaluronidase expression. Digestion products from different hyaluronidases and a hyaluronidase inhibitor were tested for their effects on OPC maturation and functional remyelination in vivo.

RESULTS: OPCs demonstrated hyaluronidase activity in vitro and expressed multiple hyaluronidases including HYAL1, HYAL2, and PH20. HA digestion by PH20 but not other hyaluronidases inhibited OPC maturation into OLs. In contrast, inhibiting HA synthesis did not influence OPC maturation. PH20 expression was elevated in OPCs and reactive astrocytes in both rodent and human demyelinating lesions. HA-digestion products generated by the PH20 hyaluronidase but not another hyaluronidase inhibited remyelination following lysolecithin-induced demyelination (Chemical-induced demyelination). Inhibition of hyaluronidase activity lead to increased OPC maturation and promoted increased conduction velocities through lesions.

INTERPRETATION: We determined that PH20 is elevated in demyelinating lesions and that increased PH20 expression is sufficient to inhibit OPC maturation and remyelination. Pharmacological inhibition of PH20 may therefore be an effective way to promote remyelination in multiple sclerosis.

It is thought that the local environment around MS lesions is part of the reason why immature oligodendrocytes cannot mature and make be oligodendrocytes that myelinate demyelinated axons to cause repair. 

This would stop the action of of any stem cells that could be transplanted into cause repair and therefore changing this environment to make it conducive to repair is what we want.

Hyaluronic acid is part of the matrix (tissue scaffolding) that is present in and around MS lesions. In this study they found that the hyaluronic acid (hyaluronan) did not prevent the differentiation of myelin-forming cells. Rather, breakdown products generated by a specific enzyme that breaks down hyaluronic acid, called a hyaluronidase, contribute to the remyelination failure. 

The hyyaluronidase enzyme that blocked this effect was called PH20 also known as SPAM1. This enzyme is highly elevated in brains of MSers and in the nervous systems of animals with an MS-like disease, notably the astrocytes that form the scar in MS. By blocking hyaluronidase activity, they could promote myelin-forming cell differentiation and remyelination in the mice with the MS-like disease and enhance the transfer of electrical activity. 

Therefore, if we can have a drug that blocks this SPAM1 then we have a way that may allow the immature oligodendrocytes that are in and around MS lesions to repair. Whether this is sufficient to do this by itself remains to be found but it is a very interesting approach that adds to the number of targets that could promote remyelination.