- While disease modifying therapies (DMTs) for MS reduce inflammation and slow progression, the body has limited capacity to repair myelin, leading to irreversible damage to myelin and nerve fibres.
- Sphingosine-1-phosphate (S1P) receptor modulators used to reduce inflammation in MS are mimics of S1P that naturally occurs in our bodies, and there is evidence that they may promote myelin repair.
- MS Australia-supported researcher, Associate Professor Anthony Don, has investigated whether naturally occurring S1P in our bodies is important for protection against demyelination and is essential for myelin repair after demyelination.
What is known about MS disease progression and the treatments available?
Damage to myelin, the insulating sheath of nerve fibres, is a pathological hallmark of MS. This can interrupt the movement of electrical signals from the brain to other parts of the body and subsequently results in a range of symptoms, including loss of motor function, reduced thinking and memory, and pain, to name a few.
DMTs for MS can dampen down the immune system, reducing inflammation and demyelination in relapsing remitting MS. While this slows disease progression, the body’s ability to repair myelin is limited. People with relapsing remitting MS eventually progress to secondary progressive MS, which is characterised by irreversible damage to myelin and nerve fibres. There is a need for treatments that promote the survival of cells that produce myelin, called oligodendrocytes, and myelin repair (remyelination) to restore neurological function in people living with MS.
There is a group of drugs used to treat MS called sphingosine-1-phosphate (S1P) receptor modulators, which includes Gilenya (fingolimod), Mayzent (siponimod) and the newer addition, Zeposia (ozanimod). These three drugs mimic naturally occurring S1P in our bodies. They are immunosuppressive, in which they dampen down the immune system, therefore reducing inflammation in MS. There is evidence that some of these drugs can also protect against the loss of oligodendrocytes and promote remyelination in laboratory models of MS. What is unknown is whether S1P naturally occurring in our bodies is important in protecting against demyelination and is necessary for remyelination after a demyelinating event.
What did the researchers investigate?
Published in Glia, MS Australia-supported researcher, Associate Professor Anthony Don, and his team investigated the requirement for a protein called SphK2, which makes S1P in the brain, for the survival of oligodendrocytes, remyelination and protecting against demyelination using laboratory models of MS. To do this, the researchers “switched off” SphK2 in laboratory models of MS and compared this to laboratory models of MS where SphK2 was not switched off.
Is this protein (SphK2) essential for remyelination after a demyelinating event?
The researchers found that demyelination was much more severe in laboratory models of MS deficient in this protein compared to models of MS that had this protein. When demyelination ceased in these models, remyelination occurred in the presence of SphK2 but not in the absence of it. Markers (signs) of myelin were also significantly lower in laboratory models of MS deficient in this protein, even after demyelination ceased. These findings suggest that the protein SphK2 is essential for remyelination.
Does this protein (SphK2) protect against the loss of mature oligodendrocytes?
To address this, the researchers investigated whether the absence of this protein affected the number of mature oligodendrocytes in laboratory models with MS and without MS. In laboratory models without MS, deficiency of this protein did not affect the number of mature oligodendrocytes in the brain.
In laboratory models of MS, the researchers found greater loss of mature oligodendrocytes in the brain in the absence of this protein. Once demyelination stopped, oligodendrocytes recovered in the corpus callosum (the region that connects each side of the brain) in both the presence and absence of SphK2. In contrast, oligodendrocytes did not recover in the cortex (the outer layer of the brain) once demyelination stopped and were significantly lower in the absence of this protein.
The researchers found that the number of precursor cells to mature oligodendrocytes, called oligodendrocyte progenitor cells (OPCs), increased in the brain in response to the loss of mature oligodendrocytes in laboratory models of MS. Interestingly, the absence of SphK2 didn’t affect this. When demyelination stopped, the number of OPCs decreased, most likely because these partially went on to restore the decreased number of oligodendrocytes.
These findings suggest that this protein, to an extent, protects against the loss of mature oligodendrocytes. They also show that this protein is not necessary for OPCs to restore oligodendrocytes but is instead necessary to produce new myelin by mature oligodendrocytes.
Does the absence of this protein (SphK2) delay remyelination?
Since mature oligodendrocytes recovered once demyelination ceased, the researchers next checked whether remyelination is delayed in the absence of SphK2. Laboratory models of MS deficient in this protein were allowed to recover from demyelination for four weeks. Despite oligodendrocytes recovering after demyelination, remyelination only occurred in the presence of SphK2. These findings suggest that the absence of SphK2 does not delay remyelination and that this protein is essential for remyelination to occur.
Does this protein (SphK2) affect the myelin sheath?
Since remyelination did not occur in the absence of this protein, the researchers thought that laboratory models deficient in SphK2 may show age-dependent myelin loss due to impaired myelin turnover. Indeed, they found older laboratory models deficient in this protein had thinner myelin. These findings show that not only is SphK2 important in remyelination in laboratory models of MS, but it appears to be essential for myelin maintenance.
These important findings show for the first time the essential role of the protein SphK2 (which makes S1P in the brain) in remyelination after a demyelinating event has occurred. This protein also plays a crucial role in myelin maintenance with age, in addition to protecting against the loss of oligodendrocytes.
As this investigation was carried out in laboratory models of MS, the research is in its very early stages.
The awarding of an MS Australia project grant to Associate Professor Don this year will extend this research further. His work will investigate if S1P treatments are myelin protective and promote remyelination, and if people living with MS are deficient in S1P in the first place.