Do viral infections trigger severe demyelinating disorders of the Central Nervous System? An assessment with a special focus on Multiple Sclerosis and Acute Disseminated encephalomyelitis

Contents

Abstract

Abriviations used

1. Introduction
1.1 Myelin
1.2 Clinical aspects
1.2.1 Multiple Sclerosis
1.2.2. Acute Disseminated Encephalomyelitis

2. The process of myelination in the Nervous system
2.1. The four stages of Schwann cell development
2.1.2. The mature myelinating Schwann cell
2.2. Myelination by Schwann cells
2.3. From precursor cell to oligodendrocyte
2.4. Myelination by oligodendrocytes
2.4.1. Definition
2.4.2. The process of myelination

3. The action potential
3.1. The axon
3.2. Generation of an action potential in health
3.3. The role of Myelin in the conduction of the action potential
3.4. Unmyelinated axons
3.5. The generation of action potential in disease

4. Multiple Sclerosis: what we know
4.1. A possible mechanism of the autoimmune reaction
4.2. Factors involved in the development of MS
4.2.1. Genetic factors
4.2.3. Environment

5. Is Multiple Sclerosis linked to viral infection?
5.1. The viral pathways
5.1.1. Viral entry into the cell
5.2.1. Viral entry into the CNS
5.2. The mechanisms causing damage
5.3. MS and the Human herpes virus 6
5.4. MS and the Epstein-Barr Virus
5.5. Evidence for a viral induction of MS

6. Acute disseminated encephalomyelitis: a disease of its own or a variant of MS?
6.1. Oligodendrocyte Pathology in myelination disorders
6.2. Axonal death

7. Animal models of demyelinating diseases
7.1. Mouse Hepatitis Virus
7.2. Theiler’s murine encephalomyelitis virus
7.2.1. The time course of the TMEV infection
7.3. Experimental autoimmune encephalomyelitis

8. Future research
8.1. Research Directed at Role of Immune System in MS
8.2. Etiology of MS
8.2.1. Immunologic
8.2.2. Environmental:
8.2.3. Infectious agents
8.2.4. Genetic:
8.3. The Future of Myelin Repair

9. Summary

Abstract

Multiple Sclerosis (MS) is a progressive, disabling, neurological illness that affects the brain and spinal cord. Nerve cells, which are usually surrounded by oligodendrocyte myelin, are damaged, die and won’t be replaced when the Central Nervous System (CNS) is inflamed. As a consequence, progressive loss of the lipid rich myelin sheath surrounding axons result in disrupted, lower fidelity action potentials and slow signal conduction.

MS is thought to have a number of causes, however, none has been identified as the true causative agent.

MS is the most common neurological disease in people below 30 and it affects more than 1 million young adults worldwide. It is five times more common in temperate climates than in tropical areas and women are affected twice as often as men are. Scientists suspect that MS develops because of the influence of genes acting together. However, a common belief held by many scientists is that not only the genetic influences, but also environmental influences, especially those of viral infections, which trigger the disease.

This review considers the evidence in existence implicating viral responsibility in the onset of myelination disorders.

Abriviations used

Abbildung in dieser Leseprobe nicht enthalten

1. Introduction

In this report the focus will be on the outline the cellular and molecular changes accompanying oligodendrocyte myelination deficit disorders in the central nervous system (CNS), in particular Multiple Sclerosis (MS). More and more people are suffering from disabilities caused by the loss of myelin.

It is important to have a cellular and molecular understanding of the disorder in order to find effective and efficient treatments. This report will review the process of myelination and the molecules involved as well as the principle function of myelin in the propagation of the action potential. Finally, scientific investigation aimed at the distinguishing characteristic features of the disease that have improved our understanding of the possible causes of the three most common demyelination diseases will be reviewed.

Initially, it is important to define the type of myelination disorder that exist.

DEMYELINATIION:

This describes the loss of existing myelin.

(i) Primary demyelination disorder: (without known or associated etiology)

This is characterised by the loss of myelin sheath without any significant reduction in axon numbers. The loss of myelin can be caused by oligodendrocyte or Schwann cell injury as well as direct myelin sheath damage.
(ii) Secondary demyelination disorder: (with known or associated etiology)

Disorders of this type are characterised by the loss of myelin sheath after axonal degeneration.

DYSMYELINATION:

Unlike demyelination, it is not the existing myelin that is degraded, but the individual fails to form normal myelin or maintain the normal myelination.

Myelination disorders occur in the CNS and in the peripheral nervous system (PNS). The causes of the CNS demyelination are the damage to the oligodendrocyte cell body and its associated myelin sheath. The exact causes of primary demyelinating diseases such as MS are unknown, as well as its underlying basis. The etiology of diseases such as Acute Disseminated Encephalomyelitis (ADEM) and Progressive Multifocal Leukoencephalopathy (PML) are known, being post infectious and associated with viral infection respectively [1].

1.1 What is Myelin?

Myelin is a high resistance specialised wrapping that insulates the axons of neurons, enabling the quick conduction and improved fidelity of electrical signals in the nervous system. Its task is the same in the CNS as in the PNS. Myelin consists mostly of lipids, such as cholesterol and phospholipids and proteins, as the Myelin Basic Protein (MBP), the myelin Proteolipid Protein (PLP) and the Peripheral Myelin Protein (PMP22). Myelin possesses its insulating properties through its lipid richness, structure, thickness and its low H2O content, which is about 40% by volume.

Depending on the type of the nerves, the extent of myelination varies, with motor and sensory nerves in the PNS being the most heavily myelinated and sympathetic nerves are unmyelinated.

As demyelinating diseases are becoming increasingly common, it is important to understand the process of myelination and how it is regulated. This is found to be different in the CNS and in PNS, where oligodendrocytes and Schwann Cells perform the myelination, respectively.

1.2 Clinical aspects

The purpose of this section is to give two examples of each type of the demyelinating diseases, with a brief summary of their clinical features and a short comparison of the latter.

1.2.1 Multiple Sclerosis

The disease is most common in females, with a ratio 2:1 (female: male). MS will affect individuals between 20-50 years of age. The symptoms include optic neuritis, unsteady gait, weakness or numbness in one or more limbs, tremor and vertigo.

1.2.2. Acute Disseminated Encephalomyelitis

The most common cause of ADEM is non-specific upper respiratory infections and varicella infections. Typical symptoms include fever, headache, vomiting and incontinence. Over 80% of known cases occur in children up to 15 years old, while in adults it is 1-3%,

Unlike MS, which is a relapsing disease, ADEM has a monophasic time course and is caused by infection of vaccination. The onset of ADEM is abrupt and more common in children lacking gender discrimination. ADEM is the more severe syndrome, as the associated mortality is 10-25%, while MS in its most severe form results in the loss of movement and mobility. Fortunately, the most severe form of MS manifests itself in only 20% of the cases, whereas 60% of individuals suffering from MS will exhibit little deficit and the final 20% moderate deficits.

2. The process of myelination in the Nervous system

As less is known about the myelination process in the CNS performed by the oligodendrocytes, a detailed description of the process performed by the Schwann cells in the PNS will be given.

2.1. The four stages of Schwann cell development

Abbildung in dieser Leseprobe nicht enthaltenFigure 1: The 4 stages of Schwann cell development, including the Proteins and Molecules expressed/suppressed

In order to become a mature myelinating Schwann cell, the precursor cell has to undergo four developmental stages (Figure 1). In the first stage, the precursor cell is a neural crest cell, which differentiates into a Schwann cell precursor cell. Following this differentiation, it will migrate out in order to contact the developing axon. Here it has already entered the second developmental stage, where it is a Schwann cell precursor. The transmission of β-Neuregulin supports the Schwann precursor cell in its development and survival. The latter is able to respond to the β-Neuregulin through erb-B3 receptors, which are crucial for the survival of the Schwann cell precursor. Experiments with erb-B3 Knockout mice have shown the importance of these receptors. Erb-B3-/- mice lack Schwann cell precursors as well as Schwann cells and lose most sensory and motor neurons during the second half of the embryonic development [2].

The timing of maturation of the Schwann cell precursors are regulated by peptides called endothelins. The Schwann cell precursor itself provides a trophic support for other cells and is thought to promote motor neuron and dorsal root ganglia (DRG) cell survival through released glial-derived neurotrophic factors (GDNF) or Neurotrophin 3 (NT3) [2].

The third stage of the development is the immature Schwann cell. Its survival is linked to the autocrine support of Growth Factors, such as Insulin-like growth factor 2 (IGF2) of Platelet-derived growth factor BB (PDGF-BB) [2]. The immature Schwann cells provide trophic support to other cells, such for the connective tissue development (Perineurium, Epineurium, and Endoneurium). Furthermore the task of ensheathing bundles of developing axons also belongs to the immature Schwann cells.

The last and final stage in the development process is the maturation of immature Schwann cell (Figure 1). The mature Schwann cells can be divided into two groups: the myelinating Schwann cell and the non-myelinating Schwann cell. The latter is formed after the myelinating Schwann cells, and expresses molecules such as neural cell-adhesion molecule (NCAM) and neurotrophin receptor p75.

2.1.2. The mature myelinating Schwann cell

The myelinating Schwann cell is the first to be formed in development of the mature Schwann cells (Figure 1). Its precursor, the promyelin Schwann cell forms an association with a single axon. At this stage, development is blocked through the inactivation of the transcription factors Oct6, which delays myelination, or Egr2, which regulates the enveloping of large-diameter axons.

The mature myelinating Schwann cell expresses myelin proteins, such as Myelin protein zero (P0), MBP and PMP, along with cholesterol biosynthetic enzymes, such as Oleoyl-Co-A synthase. Molecules such as NCAM and neurotrophin receptor p75 are down regulated at this stage. The regulation of the axonal structure and function is done through the myelin-associated glycoprotein (MAG), which is received by the axon through a kinase phosphotase cycle [3, 4].

The mature myelinating Schwann cells lose their neuregulin dependence and promote the autocrine survival by NT3, IGF2 and PDGF-BB. This autocrine survival regulation permits the Schwann cells to survive the death of an axon and to retain the function of stimulating peripheral nerve regrowth.

2.2. Myelination by Schwann cells

The Schwann cells also belong to the glia cell family. The myelination in the PNS is performed exclusively by Schwann cells and unlike the oligodendrocytes; Schwann cells myelinate only one section of an axon.

Genes involved in the myelination process by Schwann cells are Krox 20 and Pax3, the former being a zinc-finger transcription. Krox20-/- mice do not have myelinating Schwann cells. Neuregulins from the axon up regulate Krox20 in the Schwann cell precursors that they are in contact with. Pax3 is a paired domain transcription factor, which inhibits the Schwann cell differentiation. It is expressed in Schwann cell precursor and is down regulated when myelination starts. Pax3 also controls expression of MBP.

NCAM and L1 (a different Ig-class cell adhesion molecule) are also expressed in Schwann cell precursors and are both down regulated when the myelination process starts. L1 is required to initiate that process and is specific for Schwann cells.

The process of myelination through Schwann cells is very similar to the process performed by oligodendrocytes, which will be explained in detail below. It is important to note that Schwann cells themselves actually wrap around the axon, while the oligodendrocyte cell body remains free from the axon.

2.3. From precursor cell to oligodendrocyte

The oligodendrocyte precursors arise in the spinal cord and the brainstem in the ventral ventricular zone. The homologue to the Drosophila gene hedgehog in vertebrates is sonic hedgehog (shh), which plays a role in the establishment of the ventral ventricular zone and seems to be involved in the oligodendrocyte lineage.

Sox10, another transcription factor identified in the oligodendrocyte lineage, is linked almost exclusively to the oligodendrocyte lineage.

2.4. Myelination by oligodendrocytes

2.4.1. Definition

The term oligodendrocyte comes from the Greek, where “oligo” means few, “dendron” tree and “cyte” cell. This name has been chosen after the observation of these cells under the microscope show branches like a tree (Figure 2).

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Figure 2: Illustration of an oligodendrocyte

Oligodendrocytes, also called oligodendroglias belong to a class of cells in the CNS, known as the macroglia cells. The myelination in the CNS is done exclusively by the Oligodendrocytes, where a single one is able to myelinate several axons.

2.4.2. The process of myelination

In vitro, is has been seen that oligodendrocytes elaborate the formation of myelin-like structures in culture in the absence of axons. However, these myelin-like structures are not compact. In vivo, however, it is known oligodendrocytes only myelinate axons, which has been shown through studies involving staining the axons with the neuron-specific β-tubulin (TuJ1) antibody[5].

An axon is myelinated through an oligodendrocyte wrapping itself around the axon in a spiral manner, extruding the cytoplasm until the opposite membranes meet, forming a multi-layered lipoprotein coat with a node of Ranvier (Figure 2). The node of Ranvier is where the action potential is reinitiated and aids the axons in the rapid signalling events.

The speed of the signalling transduction is proportional to the thickness of the myelin sheath around the axon, while the latter is related to the diameter.

3. The action potential

The action potential is the transmission of an electrical signal from one cell to another, initiated by the depolarisation of the cell membrane. The conductance of these electrical signals is crucial to the mobility and reactions of animals, and therefore, its generation and conductance will be focused on in this section.

3.1. The axon

The axon is the tubular constituent of the neuron that connects the dendrites with the synapses. The neuron can be divided into 4 major parts: the somadendritic zone (input), the action potential initiation zone (integration), the action potential propagation zone (conduction) and the axonal output zone (output).

The action potential is initiated at the axon hillock, which is the origin of the axon, through the depolarisation of the membrane caused by a local potential.

3.2. Generation of an action potential in health

The depolarisation occurs when a physical or chemical stimulus is strong enough to increase the resting potential of –70mV to +50mV. This increase in voltage will cause the Voltage dependent Sodium channels to open and allows sodium ions to flow down their electrochemical gradient. The electric current caused by the influx of Sodium ions has the consequence of a local reversal of electric polarity of the membrane.

As the membrane potential has now become positive on the inside of the membrane, the electric gradient balances the sodium concentration gradient. At the site of the original stimulus, the depolarisation is now complete and the sodium channels close. The potassium channels sense this change in polarity and respond through an efflux of potassium ions out of the cell. This and the sodium-potassium pump will restore the resting potential. Following the depolarisation, the sodium channels cannot be stimulated for a couple of milliseconds, preventing over stimulation.

3.3. The role of Myelin in the conduction of the action potential

The primary role of Myelin is the insulation of the axons, thus, providing the saltatory conduction of signals. The wrapping of the myelin around the axons are discontinuous, generating the Nodes of Ranvier. Through the insulation of myelin, ionic exchange is prevented, so the action potential can only occur at the Nodes of Ranvier. The depolarisation of the axon causes an action potential, which jumps (“saltare”) from node to node (Figure 3).

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Figure 3: Signal transduction in health

Compared to the generation and propagation of an action potential in unmyelinated axons, this form of conduction increases the conduction velocity considerably, saving not only time but also energy. Furthermore, it illustrates the importance of Nodes of Ranvier in the transmission of nerve impulses.

3.4. Unmyelinated axons

Unmyelinated axons lack the Node of Ranvier and therefore do not perform saltatory conduction. Instead, the action potential is propagated through electrical conduction, triggered by voltage gated ion channels.

The speed of conducting in unmyelinated axons is proportional to the diameter of the axon. The thicker the axon is, the faster the propagation of the impulse is going to be. Furthermore; the action potential will decay with time, depending on the length and the diameter of axon.

3.5. The generation of action potential in disease

It has been mentioned previously that myelinated axons transmit an action potential faster than unmyelinated axons through salutatory conduction. Diseases affected by the change in the action potential propagation (Figure 4) are diseases such as MS, Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s. People suffering from MS have a lower conduction velocity than normal individuals, with an estimation of 80% decrease of velocity in small fibres and 5% in large fibres. Additionally, the signals are no longer focused and this low fidelity prevents rapid conductance. The causes for MS will be discussed later on in this report.

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Figure 4: Signal transmission in disease

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