1 November 2016
Multiple sclerosis (MS) causes the immune system to attack the central nervous system leading to a gradual loss of function as neurons lose their ability to communicate. Scar formation at these damaged sites directly interferes with neuronal repair processes, but researchers led by Voon Wee Yong at the University of Calgary in Canada have identified a potential strategy for promoting regeneration.
In MS, the immune cells strip away a protein called myelin, which forms a coating around the axons of neurons and helps preserve the strength and speed of neuronal signalling. Yong and colleagues had uncovered evidence that molecules called chondroitin sulfate proteoglycans (CSPGs) might be critically involved in this myelin loss. “The role of CSPGs at sites of central nervous system damage is unclear and may even involve trying to limit the area of injury,” says Yong, “but the consequence is a scar-forming material that impedes attempts at remyelination.”
CSPGs interfere with the growth of oligodendrocyte precursor cells (OPCs), which ultimately coordinate the replacement of lost myelin. The researchers initially set out to identify drugs that might counter this effect. However, the inhibitory activity of accumulated CSPGs proved too potent to overcome and OPC growth remained stalled in cell culture experiments regardless of the treatment used.
As an alternative, Yong and colleagues screened for compounds that prevent this accumulation. CSPGs are synthesized by cells called astrocytes. After treating cultured astrocytes with various molecules, the researchers identified one that greatly reduced CSPG production. This compound, fluorosamine, proved capable of restoring OPC growth in both cell culture and rodent models and even facilitated the repair of demyelinated nerves. Intriguingly, fluorosamine also appeared to directly suppress damaging immune activity in a rodent model of MS. “This approach therefore represents a two-pronged attack on the disease,” says Yong.
The details on the mechanisms by which specific CSPGs inhibit OPC function remain unclear. Yong and colleagues now intend to delve into these questions and to pursue the development of even better inhibitors. He notes that the implications of this work could reach well beyond MS to encompass other disorders of the central nervous system. “CSPGs are laid down following most types of neurological insults,” says Yong. “In traumatic spinal cord injury, for example, CSPGs can inhibit axonal regeneration at injury sites, and so our approach may benefit this field as well.”
Keough, M.B., Rogers, J.A., Zhang, P., Jensen, S.K., Stephenson, E.L. et al. An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nat. Commun. | article