Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

Abstract

Axonal degeneration determines the clinical outcome of multiple sclerosis (MS), and is thought to result from exposure of denuded axons to immune-mediated damage. We challenge this view after finding in MS and its mouse models that myelin itself increases the risk of axons to degenerate under inflammatory conditions. We propose a model for demyelinating diseases in which for axons that remain myelinated, and thus shielded from the extracellular milieu, dependence from oligodendroglial support turns fatal in an autoimmune disease environment.

Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes in PLP1 mutant mice

“…Indeed, axons that remain myelinated under inflammatory conditions have recently been proposed to be at higher risk for degeneration. 57 The fact that FTY720 treatment attenuated T cell recruitment and axonal damage but did not significantly affect myelin integrity in PLPmut mice also argues against the possibility of axon degeneration being a consequence of demyelination. Because a direct T cell attack on axons is also difficult to explain when considering the reduced damage in mosaic females, further studies should explore the detrimental T cell-driven reactions of PLPmut oligodendrocytes.…”

Remyelination protects neurons from DLK-mediated neurodegeneration

“…Collectively, these gain and loss of function experiments provide direct experimental evidence that remyelination rate is a critical determinant of subsequent neurodegeneration. These experiments provide an important counterpoint to recent findings that damaged or dysfunctional myelin is also a risk factor for axonal degeneration 56 . Axonal damage in EAE is more prevalent in myelinated axons relative to their demyelinated counterparts and the hypomyelinated Mbp mutant mouse have less axonal damage in EAE 56 .…”

“…These experiments provide an important counterpoint to recent findings that damaged or dysfunctional myelin is also a risk factor for axonal degeneration 56 . Axonal damage in EAE is more prevalent in myelinated axons relative to their demyelinated counterparts and the hypomyelinated Mbp mutant mouse have less axonal damage in EAE 56 . These animal studies suggest a substantial challenge for targeting myelin in MS; during the early stages of the disease on one hand dysfunctional myelin is damaging to the axon and needs to be cleared, on the other hand, prolonged demyelination is also detrimental to both the function and viability of the neuron.…”

“…Comparing the optic nerves of Myrf ΔiPlp1 mice, which feature considerable remyelination, to Myrf ΔiSox10 mice with remyelination failure, allows for a clear assessment of the role of remyelination in neuronal integrity. We examined the number of axons with accumulated organelles, indicative of impaired axonal transport 52,53 , as an indicator of axonal injury (Figure 4A). Following demyelination in both Myrf ΔiPlp1 and Myrf ΔiSox10 mice at 10 weeks post tamoxifen there is an increase in the number of axons with accumulated organelles (Figure 4B).…”

Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed myelinating oligodendrocytes inPLP1mutant mice

“…Combined with the observation that axonal damage in aged and myelin mutant mice depends on granzyme B, we propose that the population of oligodendrocytes upregulating Serpina3n to counteract T cell cytotoxicity, demyelination, and cell death is more detrimental to axonal integrity. Indeed, axons that remain myelinated under inflammatory conditions have recently been proposed to be at higher risk for degeneration 54 . The fact that FTY720 treatment attenuated T cell recruitment and axonal damage but did not significantly affect myelin integrity in PLPmut mice also argues against the possibility of axon degeneration being a consequence of demyelination.…”