Myelin Insulation and Risk of Neuron Degeneration in Autoimmune Environments
Post by Meredith McCarty
The takeaway
In the progression of autoimmune diseases such as multiple sclerosis, the degeneration of axons in the central nervous system leads to irreversible damage. Myelin sheaths encapsulating axons increase the risk of axonal degeneration in an autoimmune environment.
What's the science?
Multiple sclerosis (MS) is an inflammatory autoimmune disorder that affects the central nervous system and is characterized by axonal degeneration. Myelination, or the process by which oligodendrocytes encapsulate a neuron’s axons with an insulating sheath of myelin, is largely considered to serve an insulating and predominantly protective role for axons. Based on this assumption, demyelination, or the destruction of the myelin sheath, has been proposed as a likely cause of the axonal degeneration seen in autoimmune disorders. However, recent evidence that axonal damage actually occurs before the onset of demyelination suggests a more complex role for myelination in autoimmune disorders. This week in Nature Neuroscience, Schäffner, and colleagues utilize MS human biopsies and mouse models of demyelinating disease to investigate the role of demyelination and oligodendrocyte function in axonal degeneration.
How did they do it?
The authors first measured the relationship between axonal damage and demyelination in human MS. They performed electron microscopy on 4 MS biopsies in order to quantify the degree of demyelination of axons surrounding the lesions. They compared how the degree of demyelination correlated with the abundance of lesions and accumulation of organelles and condensed axoplasm, as measures of irreversible axonal damage.
In order to study the relationship between myelination, oligodendrocyte function, and acute inflammatory environments, the authors utilized several experimental mouse models and induced experimental autoimmune encephalomyelitis (EAE) to study axon survival. First, to understand the temporal dynamics of axon degeneration, they induced EAE in mice via immunization. They quantified the proportion of myelinated and demyelinated damaged axons and characterized changes in myelin structure using electron microscopy and immunohistochemistry. To understand changes in gene regulation in EAE, the authors analyzed RNA sequencing datasets.
Next, in order to test whether demyelination could actually improve axon outcome, the authors used a cuprizone mouse model where axon demyelination occurs at an increased rate over time and measured changes in axon organelle accumulation. Lastly, in order to directly test whether the degree of myelination correlates with axonal damage, the authors used a mouse model with decreased expression of myelin basic protein (MBP). These hMbp mice exhibit an increased proportion of unmyelinated axons. They compared the disease progression and degree of axonal damage in hMbp mice relative to controls in an induced EAE environment.
What did they find?
The authors found that in both human and mouse models, irreversible axonal damage was restricted to myelinated axons. These damaged axons displayed increased organelle accumulation and highly condensed axoplasm, which are early biomarkers of axonal degeneration. The physical characteristics of myelin in damaged axons were found to be reflective of the dysfunctional movement of cellular materials to the axon by oligodendrocytes. They found evidence for the downregulation of RNA sequences essential for many cellular processes in EAE. In the cuprizone mouse model of axon demyelination, the authors found a decline in organelle accumulation in demyelinating axons, which suggests that demyelination can improve axonal survival.
When directly comparing axonal damage in hMbp mice in an EAE environment, the authors found significantly less axonal damage, fewer axons with organelle accumulation and condensed axoplasm, and overall better disease outcome relative to the control group. After ruling out differences in immunological response across these experimental groups, they found that axonal damage was limited to myelinated axons, even in a mouse model with an artificially increased proportion of demyelinated axons. Based on these data, the authors hypothesize that the progression to irreversible axonal degeneration is likely due to the accumulation of organelles and condensed cytoplasm, a process that would be prevented with efficient demyelination of the axon. They propose that oligodendrocyte dysfunction and the failure of efficient demyelination leads to this irreversible axonal damage.
What's the impact?
This study untangled the contradictory role of axonal myelination in the axonal damage characteristic of autoimmune diseases such as multiple sclerosis. Through untangling the molecular mechanisms involved in this axonal degeneration, this study puts forth novel theories as to the crucial role of oligodendrocytes and efficient demyelination of axons in an acute inflammatory environment. Future work building off of these findings has enormous implications for identifying new targets for therapeutic intervention to prevent axonal damage early in disease progression.
