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P0

Myelin protein zero (P0), also known as MPZ, is a type I transmembrane glycoprotein that serves as the predominant structural component of the myelin sheath in the peripheral nervous system (PNS).^[1] Expressed primarily by Schwann cells, P0 constitutes approximately 50% of the total protein content in compact PNS myelin, where it plays a critical role in stabilizing the multilayered myelin structure through homophilic adhesion between extracellular domains of apposed membranes.^[2] Its single immunoglobulin-like domain facilitates intercellular interactions that are essential for proper myelination, ensuring efficient nerve impulse conduction.^[3] Structurally, P0 features an N-terminal extracellular immunoglobulin-like domain, a single transmembrane helix, and a positively charged cytoplasmic tail, which together enable its adhesive and compaction functions during myelin formation.^[4] In the PNS, Schwann cells synthesize and traffic P0 to the plasma membrane, where it accumulates to drive the radial growth and compaction of myelin lamellae, a process vital for insulating axons and supporting rapid signal transmission.^[5] Beyond adhesion, P0 exhibits multifaceted roles, including signaling capabilities that regulate Schwann cell differentiation and myelin maintenance, with phosphorylation of its cytoplasmic tail modulating these interactions.^[6] Mutations in the MPZ gene, which encodes P0, are associated with a spectrum of hereditary demyelinating neuropathies, most notably Charcot-Marie-Tooth disease type 1B (CMT1B), a common form of inherited peripheral neuropathy affecting motor and sensory nerves.^[1] These genetic alterations can disrupt P0's adhesive properties or trafficking, leading to unstable myelin, axonal degeneration, and progressive muscle weakness, sensory loss, and foot deformities.^[2] Research into P0's structure and function continues to inform therapeutic strategies for these disorders, highlighting its foundational importance in neurobiology.^[3]

Molecular Biology

Gene and Expression

The MPZ gene, encoding myelin protein zero (P0), is located on chromosome 1q23.3 in humans.^[7] It spans approximately 6 kb of genomic DNA and consists of 6 exons in its canonical transcript.^[8] Transcription of the MPZ gene is tightly regulated by Schwann cell-specific promoters and enhancers that activate during peripheral nerve development.^[9] These regulatory elements respond to developmental cues, ensuring precise spatiotemporal control of gene activation in myelinating Schwann cells.^[10] MPZ mRNA expression reaches its peak during the active myelination phase in Schwann cells, aligning with the formation and compaction of peripheral nerve myelin sheaths.^[11] Post-transcriptional regulation by microRNAs further modulates MPZ mRNA stability and translation, contributing to the fine-tuning of protein levels essential for myelination.^[12] The MPZ gene is evolutionarily conserved across vertebrates, with orthologs present in a wide range of species including mammals, birds, and fish.^[13] Mammalian orthologs exhibit particularly high sequence similarity, reflecting the conserved function of P0 in peripheral nervous system myelination.^[14]

Protein Structure

P0 is a 219-amino-acid mature glycoprotein with a molecular weight of approximately 28 kDa, arising from post-translational processing of the 248-amino-acid precursor that includes cleavage of a 29-amino-acid signal peptide.^[15] It features a single N-linked glycosylation site at Asn93 in the extracellular domain, which contributes to its stability and function in myelin.^[16] The protein architecture comprises three principal domains: an extracellular immunoglobulin-like domain (residues 1–124) that mediates homophilic adhesion between apposing myelin membranes; a single transmembrane helix (residues 125–147) that anchors P0 in the lipid bilayer; and a cytoplasmic tail (residues 148–219) enriched with basic residues such as lysine and arginine, which supports electrostatic interactions with negatively charged phospholipid headgroups.^[1] The extracellular domain adopts a typical immunoglobulin variable fold, characterized by two beta-sheets stabilized by an intramolecular disulfide bond between Cys20 and Cys97.^[17] Oligomerization of P0 is essential for myelin compaction, with the extracellular domain forming homodimers through non-covalent interfaces observed in crystal packing, while the full-length protein assembles into membrane-embedded tetramers, further stabilized by hydrogen bonds at the adhesion interface and transmembrane interactions.^[18]^[2] Insights into this quaternary structure derive from X-ray crystallography of the rat extracellular domain (PDB ID: 1NEU) at 1.9 Å resolution, which reveals a beta-sheet-rich Ig fold with surface features conducive to homophilic binding.^[17] A crystal structure of the human extracellular domain (PDB ID: 3OAI) confirms the conserved Ig fold at 2.0 Å resolution.^[19]

Biological Function

Role in Myelination

Myelin protein zero (P0), also known as MPZ, is primarily expressed by Schwann cells in the peripheral nervous system (PNS), where it serves as the predominant structural component of compact myelin. Constituting approximately 50% of all proteins in peripheral myelin sheaths, P0 plays a pivotal role in enabling the tight compaction of myelin layers that insulate axons.^[20] This abundance allows Schwann cells to form multilayered myelin wraps efficiently during development, ensuring the structural integrity required for rapid nerve impulse transmission.^[4] The adhesive properties of P0 drive the myelination process through homophilic interactions between its extracellular immunoglobulin-like domains on apposed membranes. These interactions mediate the initial adhesion and subsequent spiraling of Schwann cell processes around the axon, promoting the formation of the intraperiod line in compact myelin.^[21] Complementing this, the cytoplasmic tail of P0, enriched with basic residues such as lysine and arginine, facilitates adhesion in the cytoplasmic compartment of compact myelin via electrostatic forces with negatively charged phospholipid heads on opposing intracellular membranes of Schwann cell layers.^[3] This dual mechanism—extracellular homophilic binding and intracellular electrostatic adhesion—ensures the stability and periodicity of the myelin sheath.^[22] P0's contributions are essential for optimizing nerve conduction velocity in the PNS. In mouse models with targeted disruption of the Mpz gene encoding P0, severe hypomyelination occurs, characterized by thinly wrapped or unmyelinated axons, leading to tremors, impaired motor coordination, and reduced conduction speeds.^[23] These findings underscore P0's indispensable function in myelin assembly and maintenance, without which the PNS fails to achieve functional insulation.^[24]

Molecular Interactions

Myelin protein zero (P0), the predominant protein in peripheral nervous system myelin, primarily mediates adhesion through homophilic interactions between its extracellular immunoglobulin-like domains on apposing Schwann cell membranes. These interactions stabilize the compact structure of the myelin sheath by bridging extracellular surfaces, forming hydrogen bonds and ionic contacts, such as those involving residues Arg74, His81, and Ala76. Recent structural studies (as of 2023) have confirmed these interactions at the atomic level, elucidating P0's role in membrane stacking.^[25]^[26]^[27] P0 associates closely with cholesterol and other lipids within myelin membranes, localizing to cholesterol-enriched lipid rafts that enhance membrane stability and compactness. This lipid interaction modulates membrane fluidity, ensuring the tight apposition of myelin layers, with disruptions in cholesterol levels impairing P0 trafficking and myelin assembly. P0 also synergizes with other myelin proteins, such as myelin basic protein (MBP) and peripheral myelin protein 2 (P2), to promote multilayer formation (as of 2024).^[26]^[28]^[22] Post-translational modifications, particularly phosphorylation in the cytoplasmic domain, regulate P0's interaction dynamics. The cytoplasmic tail undergoes phosphorylation on tyrosine residues, such as Tyr220 within the YAML motif, mediated by tyrosine kinases, as well as on serine residues like Ser228 and Ser233 by protein kinase C (PKC). These modifications alter P0's adhesive properties and signaling efficiency during myelination, preventing aberrant aggregation and supporting proper myelin sheath formation.^[29]^[30]

Clinical Significance

Associated Diseases

Mutations in the MPZ gene, which encodes myelin protein zero (P0), are primarily associated with a spectrum of hereditary peripheral neuropathies characterized by demyelination and impaired nerve conduction. These disorders include Charcot-Marie-Tooth disease type 1B (CMT1B), Dejerine-Sottas syndrome (DSS), and Roussy-Levy syndrome, with varying severity and onset depending on the specific mutation. Globally, MPZ mutations account for approximately 5% of all Charcot-Marie-Tooth (CMT) cases, though prevalence can be higher in certain populations due to founder effects, such as the T124M variant in Japanese cohorts (8-17% of CMT families) and the R98H variant in some Chinese families (3%).^[31]^[32] Charcot-Marie-Tooth disease type 1B (CMT1B) is an autosomal dominant demyelinating neuropathy caused by MPZ mutations, representing 10-12% of CMT type 1 cases. It typically presents in adolescence or early adulthood with progressive distal muscle weakness and atrophy in the legs and feet, leading to gait difficulties, high-arched feet (pes cavus), and sensory loss to touch, pain, or temperature. Hand involvement often follows, with reduced reflexes and occasional foot deformities like hammertoes; the condition progresses slowly, rarely affecting life expectancy but impacting mobility and quality of life.^[33]^[34]^[35] Dejerine-Sottas syndrome (DSS), also known as CMT type 3, is a severe form of congenital hypomyelination frequently linked to MPZ mutations, often acting in a dominant-negative manner. Symptoms emerge in infancy or early childhood, including delayed motor milestones such as walking (often not achieved until preschool age or later), profound distal weakness in the legs and arms, sensory deficits, absent reflexes, and hypertrophic nerves detectable on examination. Affected individuals typically experience rapid progression to wheelchair dependence by early childhood, with complications like scoliosis, foot deformities, ataxia, and potential respiratory issues due to profound disability.^[36]^[35]^[34] Roussy-Levy syndrome represents a phenotypic variant of CMT1B associated with specific MPZ mutations, distinguished by prominent tremor and ataxia alongside core neuropathy features. Onset occurs in early childhood, with initial symptoms of gait ataxia, distal lower limb weakness, and upper limb intention tremor, progressing to areflexia, pes cavus, sensory impairment, and mild skeletal deformities like kyphoscoliosis. Motor nerve conduction velocities are markedly reduced (<20 m/s), and the condition advances slowly, emphasizing cerebellar-like features in addition to peripheral nerve involvement.^[37]

Mutations and Pathophysiology

Mutations in the MPZ gene, which encodes myelin protein zero (P0), are a major cause of demyelinating neuropathies such as Charcot-Marie-Tooth disease type 1B (CMT1B). Common mutation types include missense variants, which often affect the extracellular immunoglobulin-like domain; nonsense and frameshift mutations leading to truncated proteins; and splice-site variants that disrupt normal mRNA processing.^[38]^[39] Missense mutations, such as p.Asp109Asn, disrupt the Ig-fold structure of P0, resulting in abnormal myelin sheath thickening and severe early-onset phenotypes like Dejerine-Sottas syndrome (DSS). Nonsense and frameshift mutations, including those causing premature stop codons or shifts in reading frame (e.g., p.Asp104ThrfsTer14), typically lead to haploinsufficiency by reducing overall P0 levels, contributing to milder, late-onset CMT1B with predominantly sensory involvement. Splice-site variants, such as c.449-1G>T, cause aberrant exon skipping or retention, further decreasing functional P0 expression and myelin stability.^[40]^[38]^[41] Pathogenic mechanisms of MPZ mutations vary by variant type and location. Gain-of-function effects predominate in many missense mutations, where misfolded P0 accumulates in the endoplasmic reticulum (ER), triggering ER stress and the unfolded protein response (UPR) via pathways like PERK and IRE1, leading to Schwann cell apoptosis and dysmyelination. Loss-of-function mechanisms, common in truncating mutations, impair P0's homophilic adhesion properties essential for compact myelin formation, resulting in reduced myelin compaction and axonal support. Dominant-negative effects occur when mutant P0 oligomers trap wild-type P0, inhibiting its trafficking to the myelin sheath and exacerbating dysfunction in heterozygous states.^[42]^[38]^[42] Animal models have elucidated these mechanisms. Transgenic mice harboring the p.Thr124Met missense mutation replicate key features of CMT1B, including hypomyelination, segmental demyelination, and slowed nerve conduction velocities due to disrupted non-compact myelin domains like paranodes and Schmidt-Lanterman incisures. These models demonstrate UPR activation and Schwann cell pathology, providing insights into therapeutic targets like ER stress modulation.^[43] Certain MPZ variants exhibit incomplete penetrance, where not all carriers develop clinical neuropathy, influenced by genetic modifiers (e.g., other neuropathy-associated loci) and environmental factors such as age or metabolic stress. This variability underscores the multifactorial nature of MPZ-related pathophysiology. As of 2025, preclinical research into gene editing and ER stress inhibitors holds promise for treating MPZ mutation-associated neuropathies.^[44]^[45]

References

[1]
MPZ - Myelin protein P0 - Homo sapiens (Human) | UniProtKB
Is an adhesion molecule necessary for normal myelination in the peripheral nervous system. It mediates adhesion between adjacent myelin wraps and ultimately ...
[2]
Molecular structure and function of myelin protein P0 in membrane ...
Jan 24, 2019 · Myelin protein zero (P0; also known as MPZ) is the most abundant protein in PNS myelin. It resides in compact myelin and spans the myelin ...
[3]
How Does Protein Zero Assemble Compact Myelin? - PMC
Myelin protein zero (P0), a type I transmembrane protein, is the most abundant protein in peripheral nervous system (PNS) myelin.
[4]
Myelin protein zero - the structural foundation behind peripheral ...
Feb 10, 2023 · P0 is the most abundant PNS myelin protein, at up to 50% of total protein, and its accumulation in membranes eventually forms stable compact myelin.
[5]
Myelin protein zero/P0 phosphorylation and function require an ...
The major protein component of myelin in the PNS is myelin protein zero (P0), a single-pass transmembrane molecule containing one Ig-like loop in the ...
[6]
Myelin Protein Zero - an overview | ScienceDirect Topics
The major and most abundant myelin protein produced by myelinating Schwann cells is myelin protein zero or P0 [23]. The gene for myelin protein zero, MPZ (aka ...
[7]
4359 - Gene ResultMPZ myelin protein zero [ (human)] - NCBI
Sep 5, 2025 · Within 94 MPZ gene mutations reported up to now, only a few were identified in the exon 4 of the MPZ gene. In this study we have identified ...
[8]
Homo sapiens myelin protein zero (MPZ), transcript variant 1, mRNA - Nucleotide - NCBI
- **Number of Exons:** 6
[9]
Direct Regulation of Myelin Protein Zero Expression by the Egr2 ...
Transgenic experiments using 1.1 kb of the Mpz promoter have displayed low levels of Schwann cell-specific expression (21, 22, 23). However, subsequent ...
[10]
Dynamic Regulation of Schwann Cell Enhancers after Peripheral ...
Dynamically regulated enhancers identify target sequences of injury-regulated transcription factors in Schwann cells.
[11]
MPZ Gene - GeneCards | MYP0 Protein
This gene is specifically expressed in Schwann cells of the peripheral nervous system and encodes a type I transmembrane glycoprotein that is a major ...
[12]
MicroRNA-Deficient Schwann Cells Display Congenital ...
Jun 2, 2010 · Such analyses revealed a marked downregulation of most myelin genes, including Mpz, Pmp22, Mbp, Mag, Prx, Plp1, Gjb1, and Egr2 in Dicer1 cKO ...
[13]
Gene: MPZ (ENSG00000158887) - Summary - Homo_sapiens
Chromosome 1: 161,304,735-161,309,968 reverse strand. ... This gene has 7 transcripts (splice variants), 175 orthologues, 6 paralogues and is associated with 16 ...
[14]
Phylogenetically Conserved Sequences Around Myelin P0 Stop ...
Myelin protein zero (P0, MPZ) is the main cell adhesion molecule in peripheral myelin, the sequence of which is evolutionarily highly conserved.Missing: orthologs | Show results with:orthologs
[15]
L-MPZ, a Novel Isoform of Myelin P0, Is Produced by Stop Codon ...
The P0 gene encodes a protein of 248 amino acids (aa) including a 29-aa signal sequence. Mature P0 protein (219 aa) is N-glycosylated and has an apparent ...
[16]
Glycans of myelin proteins - Wiley Online Library
Sep 12, 2014 · Human P0 is the main myelin glycoprotein of the peripheral nervous system. It can bind six different glycans, all linked to Asn93, ...
[17]
Myelin protein zero exists as dimers and tetramers in ... - PubMed
P0 oligomerization was confirmed using Western blotting, which showed monomeric P0 at approximately 30 kDa and oligomeric P0 at approximately 60 kDa and ...Missing: homodimers disulfide bonding
[18]
Myelin Protein Zero - an overview | ScienceDirect Topics
Myelin protein zero (MPZ) is defined as a key adhesive protein that is essential for the formation of myelin in vertebrates, originating from cartilaginous ...Missing: orthologs | Show results with:orthologs
[19]
Upregulation of large myelin protein zero leads to Charcot–Marie ...
Mar 13, 2020 · These results highlight the importance of an appropriate L-MPZ/P0 ratio and show that aberrant readthrough of a myelin protein causes neuropathy.Missing: orthologs | Show results with:orthologs
[20]
On the synergy between myelin proteins P0, MBP, and P2 in ...
Apr 29, 2025 · P0 functions as an adhesion molecule by a head-to-head zipper-like oligomerization of apposing Ig domains and electrostatic interactions between ...
[21]
Mouse P0 gene disruption leads to hypomyelination ... - PubMed - NIH
Mouse P0 gene disruption leads to hypomyelination ... These mice are deficient in normal motor coordination and exhibit tremors and occasional convulsions.
[22]
A nonsense mutation in myelin protein zero causes congenital ...
Protein zero (P0), encoded by the MPZ gene, is primarily expressed in Schwann cells (SCs) and is the major structural transmembrane protein in peripheral myelin ...Missing: residues | Show results with:residues
[23]
Role of Myelin P0 Protein as a Homophilic Adhesion Molecule
Apr 26, 1990 · We also show that this aggregation is mediated by homophilic binding between P0-expressing cells and that the apposing plasma membranes of these ...Missing: Zero MPZ laminin- collagen IV Fyn kinase actin cytoskeleton cholesterol lipids phosphorylation Tyr145
[24]
https://pmc.ncbi.nlm.nih.gov/articles/PMC6298235/
[25]
Peripheral Nerve Development and the Pathogenesis of Peripheral ...
What was surprising is the recent evidence that mutation of the myelin protein zero (P0) gene (MPZ) may also result in aberrant radial sorting of axons in ...
[26]
Data supporting the role of Fyn in initiating myelination in the ...
Increased expression of myelin marker proteins MPZ and CNPase in transgenic mice expressing active Fyn. (A) Tissue lysates (n=3 mouse samples) from 3-day-old ...
[27]
Overview of myelin, major myelin lipids, and myelin-associated ...
Feb 21, 2023 · For example, the disordered region of the myelin protein zero (P0) participates in developing the mature myelin membrane (Raasakka and Kursula, ...
[28]
Tyrosine phosphorylation of PNS myelin P(0) occurs in ... - PubMed
Tyrosine phosphorylation of PNS myelin P(0) occurs in the cytoplasmic domain and is maximal during early development. J Neurochem. 2000 Jul;75(1):347-54. doi ...Missing: zero | Show results with:zero
[29]
Charcot-Marie-Tooth Disease - Medscape Reference
Feb 6, 2023 · Mutations in the gene encoding the major PNS myelin protein, myelin protein zero (MPZ), account for 5% of patients with CMT disease.
[30]
Charcot-Marie-Tooth disease - Genetics - MedlinePlus
Oct 1, 2018 · For example, Roussy-Levy syndrome is a form of CMT11 with the ... Another 10 to 12 percent of individuals with CMT1 have mutations in the MPZ gene ...
[31]
Charcot-Marie-Tooth disease type 1B - Orphanet
Classification level: Disorder. Synonym(s): Prevalence: 1-9 / 100 000. Inheritance: Autosomal dominant. Age of onset: Adolescent, Adult, Childhood, Infancy.
[32]
Charcot-Marie-Tooth Hereditary Neuropathy Overview - NCBI - NIH
Jan 23, 2025 · Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy.
[33]
Dejerine-Sottas Syndrome - Symptoms, Causes, Treatment | NORD
Aug 6, 2019 · DSS is caused by changes (mutations) in several different genes. Genes associated with DSS include MPZ, EGR2, PMP22, and PRX. Mutations in ...Missing: P0 prevalence
[34]
180800 - ROUSSY-LEVY HEREDITARY AREFLEXIC DYSTASIA
Roussy-Levy syndrome is an autosomal dominant disorder characterized by early onset of prominent ataxia followed by late onset of mild motor involvement.Missing: association | Show results with:association
[35]
Loss of function MPZ mutation causes milder CMT1B neuropathy
Patients with likely MPZ loss of function due to mutations that cause haplodeficiency in MPZ have a mild, predominantly large fiber sensory neuropathy.
[36]
A novel synonymous mutation in the MPZ gene causing an aberrant ...
This is the third reported synonymous MPZ variant associated with CMT1 and affecting splicing. These data confirm the functional impact of synonymous variants ...
[37]
Peripheral myelin modification in CMT1B correlates with MPZ gene ...
In the third patient, a de novo Asp109Asn mutation was associated with abnormally thick myelin sheaths. This adds to the known list of MPZ gene mutations ...
[38]
https://pubmed.ncbi.nlm.nih.gov/33960567/
[39]
The Thr124Met mutation in the peripheral myelin protein zero (MPZ ...
We observed a missense mutation in the peripheral myelin protein zero gene (MPZ, Thr124Met) in seven Charcot-Marie-Tooth (CMT) families and in two isolated ...
[40]
Genetic Modifiers and Non-Mendelian Aspects of CMT - PMC
Sep 13, 2019 · More than half of all CMT cases are caused by five genetic mutations: PMP22 duplication (39.5%), PMP22 point mutation (1.4%), GJB1 (10.8%), MFN2 ...