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

Abstract

Axonal degeneration determines the clinical outcome of multiple sclerosis and is thought to result from exposure of denuded axons to immune-mediated damage. Therefore, myelin is widely considered to be a protective structure for axons in multiple sclerosis. Myelinated axons also depend on oligodendrocytes, which provide metabolic and structural support to the axonal compartment. Given that axonal pathology in multiple sclerosis is already visible at early disease stages, before overt demyelination, we reasoned that autoimmune inflammation may disrupt oligodendroglial support mechanisms and hence primarily affect axons insulated by myelin. Here, we studied axonal pathology as a function of myelination in human multiple sclerosis and mouse models of autoimmune encephalomyelitis with genetically altered myelination. We demonstrate that myelin ensheathment itself becomes detrimental for axonal survival and increases the risk of axons degenerating in an autoimmune environment. This challenges the view of myelin as a solely protective structure and suggests that axonal dependence on oligodendroglial support can become fatal when myelin is under inflammatory attack.

Neddylation orchestrates the complex transcriptional and posttranscriptional program that drives Schwann cell myelination

“…2, J and K) suggested an axonal pathology in Nae1 cKO mice. EM analyses supported this because we found abnormal axonal profiles (axonal swellings with organelle accumulations) (22) in Nae1 cKO mice at all ages examined (Fig. 3F), fewer large diameter sorted axons (myelinated or amyelinated) (Fig.…”

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 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. Axonal swellings with accumulated organelles are found following demyelination in both Myrf ΔiPlp1 and Myrf ΔiSox10 mice 10 weeks post tamoxifen (Figure 4A-B), indicative of impaired axonal transport, an early stage of damage 55,56 . The total number of axons did not decline by 10 weeks post tamoxifen (Figure 4C).…”

“…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).…”