Myelin is a modified cell membrane that forms a multilayer sheath around the axon. It retains the main characteristics of biological membranes, such as lipid bilayer, but differs from them in several important respects. In this review, we focus on aspects of myelin composition that are peculiar to this structure and differentiate it from the more conventional cell membranes, with special attention to its constituent lipid components and several of the most common and important myelin proteins: myelin basic protein, proteolipid protein, and myelin protein zero. We also discuss the many-fold functions of myelin, which include reliable electrical insulation of axons to ensure rapid propagation of nerve impulses, provision of trophic support along the axon and organization of the unmyelinated nodes of Ranvier, as well as the relationship between myelin biology and neurologic disease such as multiple sclerosis. We conclude with a brief history of discovery in the field and outline questions for future research.
Myelin sheath is a modified cell membrane that wraps multiple times around the nerve axon. Tight, layer-by-layer packing allows for reliable electrical insulation of axons and thereby ensures rapid propagation of nerve impulses—electromagnetic waves driven by electric potential - along the axon and reduce axonal energy consumption. Compact multilayered myelin sheath allows an increase in the velocity of propagation from less than 1 m/s to 50–100 m/s without an increase in the diameter of axons. Myelin sheath is an exclusive innovation of vertebrate organisms and may explain the larger size of vertebrates relative to nearly all other animals.
Optimum insulation depends on the types and ratios of myelin constituent lipids and proteins and myelin water fraction. If the myelin sheath is damaged, axonal insulation is disrupted, and nerve impulses along the axon slow down or fail to conduct, resulting in neurologic dysfunction. Myelin-related pathology underlies several neurogenetic diseases, such as leukodystrophies and inherited demyelinating neuropathies, and acquired neurologic diseases, such as multiple sclerosis (MS) and subacute combined degeneration. Myelin degradation also contributes to age-related cognitive decline. It is, therefore, important to understand at the molecular level the processes that underlie the formation of the myelin sheath (myelination) and the replacement of damaged areas of the sheath (remyelination).
In this review, we will discuss the general properties of myelin, focusing on the features of its composition, formation, structure, and function that differentiate it from the more conventional cell membranes. We will also address differences in myelin formation and properties in the central nervous system (CNS) and the peripheral nervous system (PNS).
The myelin sheath is typically made of up to 100 layers tightly wound on top of each other around the axon. Two characteristic periodic morphological features of the myelin sheath are alternating major dense lines and intraperiod lines. The major dense lines are ∼two to three nm wide and are formed by the closely condensed intracellular (cytoplasmic) surfaces between the inner membranes of the two lipid bilayers. The intraperiod lines are wider—4 nm - and are formed by tightly apposed extracellular surfaces of myelin sheaths.
The number of myelin layers determines the thickness of the sheath, which depends on the axon diameter: the larger the axon, the thicker the myelin sheath. The relative thickness of a myelin sheath is conventionally measured as the ratio between the inner diameter and the outer diameter of the myelin sheath–so-called the g-ratio. Thus, the thinner the myelin sheath, the closer the g-value is to 1. The optimal g-ratio depends on the requirement to optimize conduction speed and minimize conduction delays, as well as other properties of the system as a whole, such as the need to conserve volume, especially within the intracranial space. The optimal g-ratio was estimated to be ∼0.77 for CNS and ∼0.6 for PNS. Deviations from the optimal g-ratio may result in abnormal neural development and neurologic disease.
Quantitative determination of the g-ratio of myelin is done using electron microscopy; recent developments have made this less time-consuming. It is also possible to estimate g-ratio in the brain in vivo using advanced magnetic resonance imaging (MRI) techniques. In healthy subjects, the g-ratio varies by brain region, with higher myelin content in the highly interconnected ‘hub regions’ than in the peripheral connections. In patients with MS, an acquired demyelinating disorder, g-ratio-weighted nodal strength in motor, visual, and limbic regions correlates with disease severity. However, wide application of g-ratio estimation to clinical practice is hindered by the large variability of g-values obtained using various MRI techniques. Comparisons of five different methods of g-ratio estimation in healthy subjects and multiple sclerosis patients showed high variability of g-values, mostly in MS lesions, and two MRI methods did not correctly predict the degree of demyelination in MS lesions.
The nervous system is traditionally divided into CNS and PNS. The CNS is comprised of the brain, spinal cord, olfactory and optic nerves, and is myelinated by oligodendrocytes. The PNS is comprised of nerves outside of the CNS–the remaining ten pairs of cranial nerves, spinal nerve roots, and peripheral nerves, and is myelinated by a different type of glial cell—the Schwann cell. The border between central and peripheral myelin–the so-called Obersteiner-Redlich zone—lies along cranial nerves and spinal nerve roots, within a few mm of nerve root entry into the brainstem or the spinal cord. The part of the axon proximal to the Obersteiner-Redlich zone (nearer the cell body) is myelinated with central myelin made by oligodendrocytes, and the part of the axon distal to this zone (farther from the cell body) is myelinated with peripheral myelin made by Schwann cells.
A single oligodendrocyte myelinates between 40 and 60 different axons but only one segment per axon. Thus, each axon in the CNS is myelinated by multiple oligodendrocytes, and each oligodendrocyte myelinates multiple axons. Oligodendrocytes myelinate different axons to variable extents depending on axon diameter to maintain optimal g-ratio. Thus, the same oligodendrocyte will myelinate the larger axons more extensively, yielding a thicker myelin sheath compared to the smaller axons. An oligodendrocyte typically needs only about 5 h to generate all its myelin, which includes the synthesis of all the necessary proteins and lipids.
Within the PNS, Schwann cell myelinates only a single axon, not multiple axons, as do oligodendrocytes in the CNS. Peripheral axons’ often span considerable length, and many Schwann cells are required to myelinate the length of a single axon. The diameter of axons in the PNS ranges from ∼0.1 μm to ∼20 μm, while in the CNS, the axons tend to be smaller, ranging from <0.1 μm to >10 μm in diameter.
Another important distinction between oligodendrocytes and Schwann cells is that Schwann cells myelinate only axons that are greater than 1 μm in diameter, a process called ‘radial sorting’. The wider-diameter peripheral axons conduct impulses at a higher speed than narrower axons, and myelination of the wider axons allows for a further increase in the speed and distance of conducted signal. Another feature of myelin sheath found only in the peripheral nerves is Schmidt-Lanterman incisures (SLI): cytoplasmic channels that pass through myelin and connect to the cytoplasm at the edge of the myelin sheath. SLI are formed where there is no tight interaction of adjacent myelin membranes, i.e., not within compact myelin sheath. SLI has a circular-truncated cone shape and are described as ‘beads in a stretched state’.
Although CNS and PNS myelin are formed by different glial cell types, they share similar morphological structures, with some quantitative differences in their lipid composition and more substantial qualitative differences in protein composition. The differences between PNS and CNS myelin may explain why some diseases, such as acute inflammatory demyelinating polyneuropathy, affect only peripheral myelin while others, such as multiple sclerosis—only central myelin. Understanding the differences between the two types of myelin may yield clues into the pathogenesis of these disorders and the processes that underlie myelin degeneration in the nervous system.
Other glial cells—astrocytes and microglia–contribute indirectly to myelinogenesis. Astrocytes promote the development of myelinating oligodendrocytes and accelerate myelin growth. Microglia remove damaged neurons and promote recovery by eliminating degenerated myelin that accumulates with aging and disease. In early development, myelin with ultrastructural abnormalities is phagocytosed by microglia. Microglia also play a neuroprotective and regenerative role by supporting myelination of axons during development and across the lifespan. Interestingly, Schwann cells also participate in myelin clearance after nerve injury.
In addition to creating tightly packed multilayered insulating segments called ‘internodes’ around the axon, myelin also plays a role in the assembly of the unmyelinated nodes of Ranvier (NR) between the internodes. The NRs are located roughly equidistant from each other along the axon and are the only points of contact between a myelinated axon and the extracellular environment. The main function of NR is to recharge neuron impulses, ensuring signal spreads along the entire length of the axon, which may be over a meter long in humans. Since the impulse appears to ‘leap’ from one NR to another, this process is known as “saltatory conduction”, from the Latin ‘saltus’ –a leap. The mechanism underlying saltatory conduction relies on clusters of voltage-gated Na+ and K+ channels within NR, which open and close depending on changes in the membrane potential of the NR.
Formation of ion channel cluster in the NR involves multiple players: cytoskeletal scaffold proteins actin, ankyrin G, beta IV spectrin, adhesion molecule neurofascin and others. Myelin proteins are also e
