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Myelin
Structure of simplified neuron in the peripheral nervous system with myelinating Schwann cells
Neuron with myelinating oligodendrocyte and myelin sheath in the central nervous system
Details
SystemNervous system
Identifiers
FMA62977
Anatomical terminology

Myelin (/ˈmaɪ.əlɪn/ MY-ə-lin) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon.[1][2] The myelinated axon can be likened to an electrical wire (the axon) with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Myelin ensheaths part of an axon known as an internodal segment, in multiple myelin layers of a tightly regulated internodal length.

The ensheathed segments are separated at regular short unmyelinated intervals, called nodes of Ranvier. Each node of Ranvier is around one micrometre long. Nodes of Ranvier enable a much faster rate of conduction known as saltatory conduction where the action potential recharges at each node to jump over to the next node, and so on till it reaches the axon terminal.[1][3][4][5] At the terminal the action potential provokes the release of neurotransmitters across the synapse, which bind to receptors on the post-synaptic cell such as another neuron, myocyte or secretory cell.

Myelin is made by specialized non-neuronal glial cells, that provide insulation, and nutritional and homeostatic support, along the length of the axon. In the central nervous system, myelination is formed by glial cells called oligodendrocytes, each of which sends out cellular extensions known as foot processes to myelinate multiple nearby axons. In the peripheral nervous system, myelin is formed by Schwann cells, which myelinate only a section of an axon. In the CNS, axons carry electrical signals from one nerve cell body to another.[6][7] The "insulating" function for myelin is essential for efficient motor function (i.e. movement such as walking), sensory function (e.g. sight, hearing, smell, the feeling of touch or pain) and cognition (e.g. acquiring and recalling knowledge), as demonstrated by the consequence of disorders that affect myelination, such as the genetically determined leukodystrophies;[8] the acquired inflammatory demyelinating disease, multiple sclerosis;[9] and the inflammatory demyelinating peripheral neuropathies.[10] Due to its high prevalence, multiple sclerosis, which specifically affects the central nervous system, is the best known demyelinating disorder.

History

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Myelin was first described as white matter fibres in 1717 by Vesalius, and first named as myelin by Rudolf Virchow in 1854.[11] Over a century later, following the development of electron microscopy, its glial cell origin, and its ultrastructure became apparent.[11]

Composition

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Transmission electron micrograph of a cross-section of a myelinated PNS axon, generated at the Electron Microscopy Facility at Trinity College, Hartford, Connecticut
Diagram of a myelinated axon in cross-section

Myelin is found in all vertebrates except the jawless fish.[12][13] Myelin in the central nervous system (CNS) differs slightly in composition and configuration from myelin in the peripheral nervous system (PNS), but both perform the same functions of insulation and nutritional support. Being rich in lipid, myelin appears white, hence its earlier name of white matter of the CNS. Both CNS white matter tracts such as the corpus callosum, and corticospinal tract, and PNS nerves such as the sciatic nerve, and the auditory nerve, which also appear white, comprise thousands to millions of axons, largely aligned in parallel. In the corpus callosum there are more than 200 million axons.[14] Blood vessels provide the route for oxygen and energy substrates such as glucose to reach these fibre tracts, which also contain other cell types including astrocytes and microglia in the CNS and macrophages in the PNS.

In terms of total mass, myelin comprises approximately 40% water; the dry mass comprises between 60% and 75% lipid and between 15% and 25% protein. Protein content includes myelin basic protein (MBP),[15] which is abundant in the CNS where it plays a critical, non-redundant role in formation of compact myelin; myelin oligodendrocyte glycoprotein (MOG),[16] which is specific to the CNS; and proteolipid protein (PLP),[17] which is the most abundant protein in CNS myelin, but only a minor component of PNS myelin. In the PNS, myelin protein zero (MPZ or P0) has a similar role to that of PLP in the CNS in that it is involved in holding together the multiple concentric layers of glial cell membrane that constitute the myelin sheath. The primary lipid of myelin is a glycolipid called galactocerebroside. The intertwining hydrocarbon chains of sphingomyelin strengthen the myelin sheath. Cholesterol is an essential lipid component of myelin, without which myelin fails to form.[18]

Myelin-associated glycoprotein (MAG) is a critical protein in the formation and maintenance of myelin sheaths. MAG is localized on the inner membrane of the myelin sheath and interacts with axonal membrane proteins to attach the myelin sheath to the axon.[19] Mutations to the MAG gene are implicated in demyelination diseases such as multiple sclerosis.[20]

Function

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Main article: Saltatory conduction
Action potential propagation in myelinated neurons is faster than in unmyelinated neurons because of saltatory conduction.

The main purpose of myelin is to increase the speed at which electrical impulses (known as action potentials) propagate along the myelinated fiber. In unmyelinated fibers, action potentials travel as continuous waves, but, in myelinated fibers, they "hop" or propagate by saltatory conduction. The latter is markedly faster than the former, at least for axons over a certain diameter. Myelin decreases capacitance and increases electrical resistance across the axonal membrane (the axolemma). It has been suggested that myelin permits larger body size by maintaining agile communication between distant body parts.[12]

Myelinated fibers lack voltage-gated sodium channels along the myelinated internodes, exposing them only at the nodes of Ranvier. Here, they are highly abundant and densely packed.[21] Positively charged sodium ions can enter the axon through these voltage-gated channels, leading to depolarisation of the membrane potential at the node of Ranvier. The resting membrane potential is then rapidly restored due to positively charged potassium ions leaving the axon through potassium channels. The sodium ions inside the axon then diffuse rapidly through the axoplasm (axonal cytoplasm), to the adjacent myelinated internode and ultimately to the next (distal) node of Ranvier, triggering the opening of the voltage gated sodium channels and entry of sodium ions at this site. Although the sodium ions diffuse through the axoplasm rapidly, diffusion is decremental by nature, thus nodes of Ranvier have to be (relatively) closely spaced, to secure action potential propagation.[22] The action potential "recharges" at consecutive nodes of Ranvier as the axolemmal membrane potential depolarises to approximately +35 mV.[21] Along the myelinated internode, energy-dependent sodium/potassium pumps pump the sodium ions back out of the axon and potassium ions back into the axon to restore the balance of ions between the intracellular (inside the cell, i.e. axon in this case) and extracellular (outside the cell) fluids.

Whilst the role of myelin as an "axonal insulator" is well-established, other functions of myelinating cells are less well known or only recently established. The myelinating cell "sculpts" the underlying axon by promoting the phosphorylation of neurofilaments, thus increasing the diameter or thickness of the axon at the internodal regions; helps cluster molecules on the axolemma (such as voltage-gated sodium channels) at the node of Ranvier;[23] and modulates the transport of cytoskeletal structures and organelles such as mitochondria, along the axon.[24] In 2012, evidence came to light to support a role for the myelinating cell in "feeding" the axon.[25][26] In other words, the myelinating cell seems to act as a local "fueling station" for the axon, which uses a great deal of energy to restore the normal balance of ions between it and its environment,[27][28] following the generation of action potentials.

When a peripheral nerve fiber is severed, the myelin sheath provides a track along which regrowth can occur. However, the myelin layer does not ensure a perfect regeneration of the nerve fiber. Some regenerated nerve fibers do not find the correct muscle fibers, and some damaged motor neurons of the peripheral nervous system die without regrowth. Damage to the myelin sheath and nerve fiber is often associated with increased functional insufficiency.

Unmyelinated fibers and myelinated axons of the mammalian central nervous system do not regenerate.[29]

Development

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Main article: Myelination
Further information: Critical period § Myelin

The process of generating myelin is called myelination or myelinogenesis. In the CNS, oligodendrocyte progenitor cells differentiate into mature oligodendrocytes, which form myelin. In humans, myelination begins early in the third trimester which starts at around week 26 of gestational age.[30] The signal for myelination comes from the axon; axons larger than 1–2 μms become myelinated.[31] The length of the internode is determined by the size of the axonal diameter.[31] During infancy, myelination progresses rapidly, with increasing numbers of axons acquiring myelin sheaths. This corresponds with the development of cognitive and motor skills, including language comprehension, speech acquisition, crawling and walking. Myelination continues through adolescence and early adulthood and although largely complete at this time, myelin sheaths can be added in grey matter regions such as the cerebral cortex, throughout life.[32][33][34]

Not all axons are myelinated. For example, in the PNS, a large proportion of axons are unmyelinated. Instead, they are ensheathed by non-myelinating Schwann cells known as Remak SCs and arranged in Remak bundles.[35] In the CNS, non-myelinated axons (or intermittently myelinated axons, meaning axons with long non-myelinated regions between myelinated segments) intermingle with myelinated ones and are entwined, at least partially, by the processes of another type of glial cell the astrocyte.[36]

Clinical significance

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Demyelination

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Further information: Demyelinating disease and Lesional demyelinations of the central nervous system

Demyelination is the loss of the myelin sheath insulating the nerves, and is the hallmark of some neurodegenerative autoimmune diseases, including multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica, transverse myelitis, chronic inflammatory demyelinating polyneuropathy, Guillain–Barré syndrome, central pontine myelinosis, inherited demyelinating diseases such as leukodystrophy, and Charcot–Marie–Tooth disease. People with pernicious anaemia can also develop nerve damage if the condition is not diagnosed quickly. Subacute combined degeneration of spinal cord secondary to pernicious anaemia can lead to slight peripheral nerve damage to severe damage to the central nervous system, affecting speech, balance, and cognitive awareness. When myelin degrades, conduction of signals along the nerve can be impaired or lost, and the nerve eventually withers.[clarification needed] A more serious case of myelin deterioration is called Canavan disease.

The immune system may play a role in demyelination associated with such diseases, including inflammation causing demyelination by overproduction of cytokines via upregulation of tumor necrosis factor[37] or interferon. MRI evidence that docosahexaenoic acid DHA ethyl ester improves myelination in generalized peroxisomal disorders.[38]

Symptoms

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Demyelination results in diverse symptoms determined by the functions of the affected neurons. It disrupts signals between the brain and other parts of the body; symptoms differ from patient to patient, and have different presentations upon clinical observation and in laboratory studies.

Typical symptoms include blurriness in the central visual field that affects only one eye, may be accompanied by pain upon eye movement, double vision, loss of vision/hearing, odd sensation in legs, arms, chest, or face, such as tingling or numbness (neuropathy), weakness of arms or legs, cognitive disruption, including speech impairment and memory loss, heat sensitivity (symptoms worsen or reappear upon exposure to heat, such as a hot shower), loss of dexterity, difficulty coordinating movement or balance disorder, difficulty controlling bowel movements or urination, fatigue, and tinnitus.[39]

Myelin repair

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Further information: Remyelination

Research to repair damaged myelin sheaths is ongoing. Techniques include surgically implanting oligodendrocyte precursor cells in the central nervous system and inducing myelin repair with certain antibodies. While results in mice have been encouraging (via stem cell transplantation), whether this technique can be effective in replacing myelin loss in humans is still unknown.[40] Cholinergic treatments, such as acetylcholinesterase inhibitors (AChEIs), may have beneficial effects on myelination, myelin repair, and myelin integrity. Increasing cholinergic stimulation also may act through subtle trophic effects on brain developmental processes and particularly on oligodendrocytes and the lifelong myelination process they support. Increasing oligodendrocyte cholinergic stimulation, AChEIs, and other cholinergic treatments, such as nicotine, possibly could promote myelination during development and myelin repair in older age.[41] Glycogen synthase kinase 3β inhibitors such as lithium chloride have been found to promote myelination in mice with damaged facial nerves.[42] Cholesterol is a necessary nutrient for the myelin sheath, along with vitamin B12.[43][44]

Dysmyelination

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Dysmyelination is characterized by a defective structure and function of myelin sheaths; unlike demyelination, it does not produce lesions. Such defective sheaths often arise from genetic mutations affecting the biosynthesis and formation of myelin. The shiverer mouse represents one animal model of dysmyelination. Human diseases where dysmyelination has been implicated include leukodystrophies (Pelizaeus–Merzbacher disease, Canavan disease, phenylketonuria) and schizophrenia.[45][46][47]

Invertebrates

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Functionally equivalent myelin-like sheaths are found in several invertebrate taxa, including oligochaete annelids, and crustacean taxa such as penaeids, palaemonids, and calanoids. These myelin-like sheaths share several structural features with the sheaths found in vertebrates including multiplicity of membranes, condensation of membrane, and nodes.[12] However, the nodes in vertebrates are annular; i.e. they encircle the axon. In contrast, nodes found in the sheaths of invertebrates are either annular or fenestrated; i.e. they are restricted to "spots". It is found on the median giant fiber of the earthworm (Lumbricus terrestris L.), which is myelinated with openings on the dorsal side.[48] The fastest recorded conduction speed (across both vertebrates and invertebrates) is found in the ensheathed axons of the Kuruma shrimp, an invertebrate,[12] ranging between 90 and 200 m/s. This is obtained by neurons 10 μm in diameter and covered by a 10 μm thick myelin.[13] (cf. 100–120 m/s for the fastest myelinated vertebrate axon).

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Myelin

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Myelin is a lipid-rich, multilayered insulating sheath that envelops the axons of many neurons in the vertebrate , formed by specialized glial cells and enabling the rapid propagation of electrical impulses through . In the (CNS), which includes the and , myelin is produced by , each of which can myelinate multiple axons, while in the peripheral nervous system (PNS), individual Schwann cells wrap around single axons to form the sheath. The structure consists of tightly compacted layers of plasma membrane spirally wound around the , creating a barrier that prevents leakage and supports signal speeds up to 100 meters per second. Compositionally, myelin is approximately 70-80% by dry weight, dominated by (about 40%), phospholipids (40%), and glycolipids like galactocerebroside (20%), which contribute to its hydrophobic, insulating properties. Key proteins include proteolipid protein (PLP) and myelin basic protein (MBP) in the CNS, accounting for over 60% of myelin proteins and stabilizing the membrane layers, and myelin protein zero (P0) in the PNS, which comprises more than 50% of proteins and mediates adhesion between layers. Functionally, myelin not only accelerates conduction by allowing impulses to "jump" between unmyelinated gaps called nodes of Ranvier but also provides metabolic support to axons, promoting their long-term health and integrity. This evolutionary adaptation, unique to jawed vertebrates, underlies the efficiency of complex nervous systems, though disruptions such as demyelination can impair signaling and lead to neurological disorders.

Structure and Composition

Molecular Components

Myelin sheaths are characterized by a high content of 70-80% and protein content of 20-30% by dry weight, with low hydration levels around 40% that enhance electrical insulation. The lipid fraction is dominated by at 25-30%, which provides structural rigidity, galactocerebroside (also known as galactosylceramide) at 20-25%, a key for membrane stability, and phospholipids such as that form the bilayer backbone.40923-X/fulltext) In the (CNS), the major proteins include proteolipid protein (PLP), comprising approximately 50% of total myelin protein and essential for membrane stabilization through its integration into lipid bilayers, and myelin basic protein (MBP), accounting for about 30% and facilitating intracellular adhesion between myelin layers. Myelin-associated glycoprotein (), present at lower levels (around 1% of total protein), plays a critical role in mediating interactions between axons and glial cells during myelination. Compositional differences exist between the CNS and (PNS), reflecting species-specific adaptations in vertebrates. In the PNS, myelin protein zero (P0) predominates at over 50% of total protein, serving as the primary structural component analogous to PLP in the CNS, while MBP is less abundant (5-18%). These molecular proportions contribute to the unique biochemical properties of myelin across neural compartments.

Ultrastructure

The myelin sheath displays a distinctive lamellar , characterized by tightly compacted, multilayered membranes that wrap spirally around the . This architecture consists of alternating bilayers interspersed with thin protein layers, forming a highly organized, concentric assembly visible under electron microscopy. The fusion of the cytoplasmic leaflets of adjacent glial cell membranes produces the major dense line, an electron-dense band approximately 3-5 nm thick, while the adhesion of the extracellular leaflets creates the less dense intraperiod line, typically 2-4 nm wide. The repeating periodicity of these lamellae, measured as the distance between consecutive major dense lines, averages 12-18 nm in the (CNS), reflecting the compact nature of oligodendrocyte-derived myelin. In the peripheral nervous system (PNS), this period is slightly wider, around 14-18.5 nm, due to the presence of distinct proteins such as myelin protein zero (P0) that influence membrane spacing compared to CNS proteins like myelin basic protein (MBP) and proteolipid protein (PLP). Myelin sheaths terminate at intervals along the , leaving exposed segments known as nodes of Ranvier, which measure 1-2 μm in length and enable the dense clustering of voltage-gated sodium and potassium channels on the axonal membrane. In PNS myelin formed by Schwann cells, non-compact regions include helical Schmidt-Lanterman incisures (also called clefts), which spiral through the sheath and maintain cytoplasmic continuity, facilitating the radial diffusion of ions, nutrients, and signaling molecules between the innermost and outermost layers. Transmission electron microscopy (TEM) has long been the gold standard for resolving myelin's , revealing sheaths with 50-200 stacked bilayers in mature, heavily myelinated , depending on axon diameter and . Recent cryo-electron (cryo-EM) studies have further illuminated the molecular details, showing how proteins like MBP and P0 bridge and stabilize bilayers through specific interactions, forming ordered lattices that maintain the sheath's integrity under physiological conditions.

Formation and Development

Cellular Mechanisms

In the (CNS), myelin is produced by , which differentiate from oligodendrocyte precursor cells (OPCs) originating in the of the embryonic . These OPCs migrate throughout the and to reach target axons, where mature can extend processes to myelinate multiple axons simultaneously, with each cell capable of forming up to 50 myelin sheaths. In the peripheral nervous system (PNS), myelination is carried out by Schwann cells, which derive from neural crest cells that undergo epithelial-to-mesenchymal transition and migrate along developing peripheral nerves. Unlike oligodendrocytes, each myelinating Schwann cell associates with and wraps a single axon in a one-to-one relationship, forming a dedicated myelin sheath around that segment. Differentiation of OPCs into oligodendrocytes is marked by the expression of transcription factors such as and Olig2, which are essential for lineage commitment, while platelet-derived growth factor receptor alpha (PDGFRα) serves as a key surface marker for OPC precursors. These markers enable identification and tracking of OPCs during development and in the adult CNS. Axon-glial signaling plays a critical role in initiating myelination, with neuregulin-1 (NRG1) acting through receptors to promote the wrapping process in both CNS and PNS. This pathway is particularly vital in the PNS for differentiation and myelin formation, and it can also trigger myelination programs in the CNS. Myelination is selective, occurring primarily on axons exceeding a threshold of approximately 0.2 μm in the CNS and 1 μm in the PNS. OPCs exhibit regional differences in distribution, with higher densities observed in white matter tracts compared to gray matter, reflecting their adaptation to areas rich in myelinated axons. This patterning supports efficient myelination in fiber-dense regions of the CNS.

Myelination Process

Myelination in the human central nervous system (CNS) initiates prenatally during the second trimester, with oligodendrocyte precursor cells (OPCs) first appearing in the forebrain around 10 gestational weeks, followed by immature oligodendrocytes between 18 and 28 gestational weeks that begin forming initial myelin sheaths around 20-24 weeks (5-6 months gestation). In the peripheral nervous system (PNS), myelination by Schwann cells commences earlier, around 15 weeks gestation, coinciding with the proliferation and differentiation of Schwann cell precursors along developing axons. This temporal difference reflects the distinct developmental timelines of CNS and PNS glial cells, with PNS myelination advancing ahead to support early peripheral nerve function. The wrapping process begins with the extension of or processes toward target , guided by axonal signals such as neuregulin-1, which triggers process ensheathment. These processes then spiral around the axon in a multi-layered fashion, forming an initial loose wrap that progresses through repetitive extension and retraction to achieve the appropriate sheath thickness. Compaction follows, where is excluded from the extracellular space between membrane layers, primarily mediated by myelin basic protein (MBP) in the CNS and myelin protein zero (P0) in the PNS, resulting in a tight, multilayered sheath that insulates the axon. This stage is energy-intensive, involving and protein synthesis to build the insulating barrier. Several regulatory factors orchestrate OPC maturation and myelination timing. Thyroid hormone accelerates OPC differentiation into mature by upregulating genes like MBP, promoting timely sheath formation during critical developmental windows. (BMP) signaling inhibits OPC differentiation, maintaining a proliferative state and suppressing premature myelination, whereas Wnt signaling promotes differentiation by enhancing β-catenin-mediated transcription of pro-myelinating factors. These pathways interact dynamically, with balanced inhibition and promotion ensuring spatially and temporally appropriate myelination. In humans, postnatal CNS myelination proceeds rapidly, peaking around 2 years of age with widespread sheath formation in major tracts, but continues more gradually into the third decade, particularly in prefrontal association areas where myelination density increases until at least 28 years. This extended timeline supports cognitive maturation, with slower myelination in higher-order regions correlating with prolonged . Adult OPCs retain the potential to proliferate, migrate, and differentiate in response to demyelinating , contributing to partial remyelination by forming new sheaths around exposed axons. However, this process is inefficient, often resulting in incomplete repair due to inhibitory environmental cues like persistent and glial scarring that hinder OPC maturation.

Physiological Functions

Electrical Insulation

Myelin facilitates rapid nerve impulse conduction through saltatory propagation, where action potentials "jump" between unmyelinated gaps known as nodes of Ranvier, rather than propagating continuously along the membrane. This mechanism dramatically increases conduction speed, with myelinated axons achieving velocities up to 150 m/s compared to 0.5–10 m/s in unmyelinated axons, representing a 10- to 100-fold enhancement. The biophysical basis of this insulation lies in myelin's composition, which provides high transverse resistivity (approximately 10^9 Ω·cm) and significantly reduces membrane capacitance by several orders of magnitude relative to bare axonal membrane. These properties minimize current leakage across the sheath and limit the charge needed to depolarize the membrane, allowing the action potential to regenerate efficiently only at the nodes, where voltage-gated sodium channels are densely concentrated (up to 2000 channels/μm²). The nodal regions are flanked by paranodal domains featuring septate-like junctions that seal the myelin loops to the , preventing diffusion and maintaining domain-specific channel localization. Just beyond, in the juxtaparanodal regions, voltage-gated potassium channels (primarily family) are clustered to repolarize the and stabilize conduction. Conduction velocity in myelinated s is proportional to (d), contrasting with the square-root dependence (v ≈ √d) in unmyelinated s, and is further optimized by myelin thickness, as quantified by the g-ratio (inner divided by total ), which averages around 0.7 for efficient insulation without excessive metabolic cost. This linear scaling enables larger s to conduct faster while keeping manageable. Additionally, myelin's insulation reduces sodium leakage during propagation, thereby lowering the metabolic demand on ATP-dependent sodium-potassium pumps for restoring ionic gradients after each .

Supportive Roles

Beyond its role in electrical insulation, myelin provides essential metabolic support to axons through a process known as metabolic coupling, where supply energy substrates such as lactate and pyruvate to sustain axonal function during periods of high activity. This transfer occurs via monocarboxylate transporters (MCTs), particularly MCT1 expressed on and MCT2 on axons, enabling the diffusion of these metabolites across the periaxonal space. Disruptions in this coupling, as seen in MCT1-deficient models, lead to axonal energy deficits and structural degeneration, underscoring its importance for long-term axonal health. Myelin also contributes to axon integrity by stabilizing the axonal and maintaining proper axon . Myelin-associated glycoprotein (MAG), located on the innermost myelin layer, interacts with axonal receptors to regulate neurofilament and cytoskeletal organization, thereby enhancing axon-myelin stability and preventing degenerative changes. Similarly, myelin basic protein (MBP) supports axonal diameter regulation; deficiencies in MBP, as observed in shiverer mice, result in abnormal axon and cytoskeletal instability due to impaired myelin compaction and trophic signaling. These mechanisms collectively protect axons from mechanical stress and ensure structural fidelity over time. In adult brains, myelin exhibits plasticity that supports synaptic function and learning, particularly through activity-dependent remodeling. For instance, tasks induce selective myelination changes along activated axons, adjusting internode lengths and sheath thickness to fine-tune conduction velocities and optimize circuit efficiency. This adaptive myelination, driven by neuronal activity signals to , correlates with improved motor performance and persists into adulthood, facilitating behavioral adaptations without forming new myelin sheaths in all cases. Myelin further offers neuroprotection against oxidative stress through its lipid components, notably plasmalogens, which act as endogenous antioxidants. These ether lipids, abundant in myelin membranes, scavenge reactive oxygen species by virtue of their labile vinyl-ether linkage, thereby shielding internodal regions from peroxidation damage and preserving axonal integrity. Plasmalogen depletion exacerbates vulnerability to oxidative insults, highlighting their role in maintaining myelin stability under physiological stress. Recent research since 2020 has illuminated myelin's involvement in , where age-related myelin decline contributes to diminished neural resilience and . Studies indicate that progressive myelin loss in aging disrupts metabolic support and plasticity, accelerating declines in executive function and , while preserved myelination correlates with better cognitive outcomes in older adults. Interventions enhancing myelination, such as exercise, have shown potential to bolster this reserve by mitigating demyelination effects.

Pathology and Disorders

Demyelination

Demyelination refers to the acquired pathological loss of the myelin sheath surrounding neuronal axons in the , often triggered by immune-mediated, inflammatory, or toxic mechanisms. In immune-mediated processes, autoreactive T cells recognize and attack myelin components such as myelin basic protein (MBP), leading to targeted destruction of the myelin sheath. Inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), exacerbate this damage by promoting and disrupting the blood-brain barrier, thereby amplifying the inflammatory cascade. Toxic mechanisms, exemplified by the cuprizone model, involve that induces selective toxicity and subsequent demyelination in regions like the , providing a non-immune paradigm for studying myelin loss. Major diseases associated with demyelination include (MS), an autoimmune disorder characterized by chronic and focal demyelination plaques, affecting an estimated 2.9 million people globally as of 2023. In MS, T-cell infiltration and release drive the autoimmune attack on myelin, resulting in axonal vulnerability and neurodegeneration. Another key condition is neuromyelitis optica (NMO), where anti-aquaporin-4 (AQP4) antibodies target , indirectly causing severe demyelination in the optic nerves and through complement activation and secondary . Endogenous repair attempts following demyelination involve the recruitment and differentiation of precursor cells (OPCs) to form new myelin sheaths around demyelinated axons. However, this process is often inefficient, particularly in chronic lesions, where tissue secretes proteoglycans (CSPGs) that inhibit OPC migration and maturation, perpetuating axonal exposure and functional deficits. Therapeutic advances target these mechanisms; for instance, ocrelizumab, a that depletes B cells to reduce antibody-mediated , received FDA approval in 2017 for relapsing and primary progressive MS. (BTK) inhibitors have been investigated for modulating microglial and potentially promoting remyelination, though evobrutinib's Phase 3 trials, completed in 2024, did not meet primary endpoints for reducing relapse rates in relapsing MS. Emerging remyelination therapies, such as PIPE-307, which targets receptors to enhance maturation, entered Phase 2 trials as of 2024. Animal models are crucial for elucidating demyelination mechanisms and testing therapies. The experimental autoimmune encephalomyelitis (EAE) model, induced by immunization with myelin antigens like MBP or proteolipid protein (PLP), simulates MS-like immune-mediated demyelination, , and relapsing-remitting disease courses in , enabling evaluation of immunomodulatory interventions.

Dysmyelination

Dysmyelination refers to a group of genetic disorders characterized by defective myelin formation or maintenance from birth, resulting in hypomyelination or abnormal myelin structure in the . These conditions arise primarily from mutations affecting genes essential for function and myelin assembly, leading to impaired neural conduction and progressive neurological deficits. Unlike demyelination, which involves the loss of pre-existing myelin, dysmyelination stems from inherent developmental failures in myelination. Key genetic causes include mutations in the proteolipid protein 1 gene (PLP1), which encodes the major myelin protein PLP1. PLP1 mutations, often X-linked, cause Pelizaeus-Merzbacher disease (PMD), a prototypical hypomyelinating disorder featuring severe to mild hypomyelination depending on the mutation type, such as duplications or missense variants. Deficiencies in myelin basic protein (MBP), another critical structural component, are associated with hypomyelinating phenotypes, though primary MBP mutations are not well-documented in humans and are primarily studied in animal models like the shiverer mouse, where they result in absent compact myelin. The of dysmyelination involves disrupted myelin sheath stability and survival. In PLP1-related disorders, mutant PLP1 proteins accumulate in the , triggering unfolded protein response and ER stress, which promotes unstable myelin sheaths and apoptosis. This leads to reduced myelin thickness relative to diameter, reflected in an increased g-ratio (typically >0.8 in affected regions), as observed in PMD . death further exacerbates hypomyelination, with iron dysregulation contributing to oxidative damage and cell loss in preclinical models. Representative clinical examples include (MLD), caused by arylsulfatase A (ARSA) deficiency, leading to accumulation that disrupts myelin formation and causes progressive dysmyelination with motor and cognitive decline. Similarly, results from galactocerebrosidase (GALC) loss, resulting in psychosine buildup, toxicity, and globoid cell infiltration with widespread hypomyelination. These lysosomal storage disorders highlight how enzymatic defects indirectly impair myelin biogenesis, manifesting in infancy with , , and developmental arrest. Diagnosis typically involves and . MRI reveals diffuse hypointensity on T1-weighted images and on T2-weighted sequences, indicating hypomyelination without significant demyelination progression over time, often with a tigroid pattern in PMD. Computed may show hypodensity, but MRI is preferred for specificity. Confirmation relies on genetic sequencing to identify PLP1, ARSA, or GALC variants, supplemented by enzyme assays for lysosomal disorders. Prognosis is generally poor, with progressive neurodegeneration leading to motor impairment, seizures, and early mortality in severe forms like classic PMD or infantile , often within the first decade. No curative treatments exist, with management limited to supportive care including and antispasmodics. Emerging approaches, such as AAV-mediated PLP1 suppression or replacement, have shown preclinical promise in restoring myelination in PMD mouse models, with trials exploring safe delivery to the CNS as of recent studies.

Comparative and Evolutionary Aspects

In Invertebrates

In annelids such as the Lumbricus terrestris, the median and lateral giant axons in the ventral nerve cord are ensheathed by glial cells that form extensive spiral wrappings, creating a myelin-like sheath composed of 60–200 layers of glial membranes around axons measuring 50–100 μm in diameter. These layers are uncompacted, lacking the tight apposition seen in myelin, and exhibit a composition rich in (15.3 μmol/g fresh tissue) that contributes to electrical insulation. This structure enables rapid continuous conduction along the giant axons, supporting escape behaviors, though without the multilamellar compaction that defines true myelin. In insects like , peripheral axons are wrapped by ensheathing (also termed wrapping ), which form tube-like coverings that envelop individual axons or small bundles without producing true compacted lamellae. These glial sheaths are lipid-enriched but lack vertebrate-specific myelin proteins such as proteolipid protein (PLP), relying instead on basic lipid-based insulation to modulate axonal diameter and prevent ephaptic . Experimental of wrapping reduces conduction from approximately 0.4 m/s to 0.13 m/s, demonstrating that these structures accelerate signaling by about threefold, enhancing precision in larval locomotion without . The nematode lacks any myelin-like structures, with its small-diameter s (typically <1 μm) relying on unmyelinated conduction. Instead, glial cells interact closely with s via gap junctions, which facilitate intercellular signaling and are essential for processes like specification in motor neurons. Recent investigations have further elucidated these glial- interactions, revealing how glia promote neurite outgrowth, maintain synaptic integrity, and influence behaviors such as through non-junctional modulation of neuronal activity. These invertebrate glial wrappings represent functional analogs to myelin, offering evolutionary precursors through lipid-mediated insulation that supports efficient, though slower and non-saltatory, conduction tailored to simpler nervous systems. conduction velocities vary, from below 1 m/s in small nervous systems to over 20 m/s in giant axons via continuous conduction, sufficing for their behavioral demands without the high-speed saltatory propagation of s, highlighting divergent adaptations in glial support.

Evolutionary Origins

The evolutionary origins of myelin trace back to ancient lipid-based insulating structures in , predating the emergence of vertebrates. In annelids such as earthworms, which appeared around 500 million years ago during the period, glial cells produce multilayered, lipid-rich sheaths that wrap around axons, providing electrical insulation and facilitating rapid nerve conduction similar to vertebrate myelin. These structures, composed of 60-70% , represent an early form of axonal ensheathment that evolved independently to support efficient neural signaling in elongated bodies. In vertebrates, true compact myelin emerged as a key innovation approximately 400 million years ago in jawed fish (gnathostomes), such as ancient cartilaginous species during the Devonian period. This form features tightly wrapped glial membranes rich in specific proteins like myelin basic protein (MBP) and proteolipid protein (PLP), which stabilize the sheath and enable saltatory conduction for faster impulse propagation. Jawless vertebrates (agnathans), including lampreys, lack compact myelin despite possessing homologs of some myelin-related genes, such as segments of the golli-MBP complex, indicating that full myelination evolved after the divergence of agnathans from the gnathostome lineage around 500 million years ago. Recent genomic analyses, including a 2023 lamprey neural cell atlas, reveal that vertebrate myelin genes were co-opted from ancient glial regulatory networks, adapting pre-existing mechanisms for ensheathment to produce the more efficient compact structure. A 2024 study further elucidated this by identifying a retrotransposon from an ancient retrovirus as crucial for activating myelin genes like Sox10 in oligodendrocytes, marking a genetic innovation in gnathostomes. This myelination provided adaptive advantages, correlating with increased body size, enhanced predatory speeds, and the of larger, more complex brains by reducing the metabolic costs of neural signaling. Unlike in annelids, arthropods lack true compact myelin, relying instead on alternative glial wrappings or giant axons for conduction , highlighting a phylogenetic gap bridged by to meet similar demands for rapid neural communication across animal kingdoms.

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