Peripheral Myelin Research Articles

Deciphering potential pharmacological mechanism of Sha-Shen-Mai-Dong decoction on primary Sjogren\u2019s syndrome

BackgroundSha-Shen-Mai-Dong decoction (SSMD) is a classical prescription widely used in primary Sjogren’s Syndrome (pSS) therapy. This study aims to explore the potential pharmacological mechanism of SSMD on pSS.MethodsActive components of SSMD were obtained from Traditional Chinese Medicine Integrative Database and Traditional Chinese Medicine Systems Pharmacology databases and targets of SSMD were predicted by Pharmmapper and STITCH database. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were carried out to explore the function characteristics of SSMD. The expression matrix of microarray of pSS was obtained from Gene Expression Omnibus and we obtained 162 differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were constructed to identify the hub targets. Principal component analysis (PCA) and molecular docking were conducted to further elucidate the possibility of SSMD for pSS.ResultsSSMD contained a total of 1056 active components, corresponding to 88 targets, among which peripheral myelin protein 2(PMP2), androgen receptor (AR) and glutamic acid decarboxylase 1(GAD1) are associated with multiple active components in SSMD and may be the core targets. Moreover, these targets were closely related to tissue pathological injury in SS, such as lacrimal gland, salivary gland and nervous system injury. GO and KEGG analysis showed that 88 targets enriched in REDOX process, transcriptional regulation and negative regulation of apoptosis process. Besides, SSMD may influence the cell proliferation, gene transcription through regulating Ras and cAMP-related signaling pathways. In addition, SSMD may show effects on immune regulation, such as macrophage differentiation, Toll-like receptor 4 signaling pathway and T-helper 1 in SS. Moreover, PPI network suggested that FN1, MMP-9 may be the hub targets in SSMD. Result of PCA and molecular docking analysis further determined the feasibility of SSMD in treating pSS.ConclusionSSMD can regulate multiple biological processes by virtue of its multiple active components, thus showing prominent advantage in the treatment of pSS. The discovery of active ingredients and targets in SSMD provides valuable resources for drug research and development for pSS.

Formation of the node of Ranvier by Schwann cells is under control of transcription factor Sox10.

The transcription factor Sox10 is an essential regulator of genes that code for structural components of the myelin sheath and for lipid metabolic enzymes in both types of myelinating glia in the central and peripheral nervous systems. In an attempt to characterize additional Sox10 target genes in Schwann cells, we identified in this study a strong influence of Sox10 on the expression of genes associated with adhesion in the MSC80 Schwann cell line. These included the genes for Gliomedin, Neuronal cell adhesion molecule and Neurofascin that together constitute essential Schwann cell contributions to paranode and node of Ranvier. Using bioinformatics and molecular biology techniques we provide evidence that Sox10 directly activates these genes by binding to conserved regulatory regions. For activation, Sox10 cooperates with Krox20, a transcription factor previously identified as the central regulator of Schwann cell myelination. Both the activating function of Sox10 as well as its cooperation with Krox20 were confirmed in vivo. We conclude that the employment of Sox10 and Krox20 as regulators of structural myelin sheath components and genes associated with the node of Ranvier is one way of ensuring a biologically meaningful coordinated formation of both structures during peripheral myelination.

Crystal and solution structure of NDRG1, a membrane-binding protein linked to myelination and tumour suppression.

N-myc downstream-regulated gene 1 (NDRG1) is a tumour suppressor involved in vesicular trafficking and stress response. NDRG1 participates in peripheral nerve myelination, and mutations in the NDRG1 gene lead to Charcot-Marie-Tooth neuropathy. The 43-kDa NDRG1 is considered as an inactive member of the α/β hydrolase superfamily. In addition to a central α/β hydrolase fold domain, NDRG1 consists of a short N terminus and a C-terminal region with three 10-residue repeats. We determined the crystal structure of the α/β hydrolase domain of human NDRG1 and characterised the structure and dynamics of full-length NDRG1. The structure of the α/β hydrolase domain resembles the canonical α/β hydrolase fold with a central β sheet surrounded by α helices. Small-angle X-ray scattering and CD spectroscopy indicated a variable conformation for the N- and C-terminal regions. NDRG1 binds to various types of lipid vesicles, and the conformation of the C-terminal region is modulated upon lipid interaction. Intriguingly, NDRG1 interacts with metal ions, such as nickel, but is prone to aggregation in their presence. Our results uncover the structural and dynamic features of NDRG1, as well as elucidate its interactions with metals and lipids, and encourage studies to identify a putative hydrolase activity of NDRG1. DATABASES: The coordinates and structure factors for the crystal structure of human NDRG1 were deposited to PDB (PDB ID: 6ZMM).

The prion protein is not required for peripheral nerve de- and remyelination after crush injury.

The cellular prion protein (PrP) is essential to the long-term maintenance of myelin sheaths in peripheral nerves. PrP activates the adhesion G-protein coupled receptor Adgrg6 on Schwann cells and initiates a pro-myelination cascade of molecular signals. Because Adgrg6 is crucial for peripheral myelin development and regeneration after nerve injury, we investigated the role of PrP in peripheral nerve repair. We performed experimental sciatic nerve crush injuries in co-isogenic wild-type and PrP-deficient mice, and examined peripheral nerve repair processes. Generation of repair Schwann cells, macrophage recruitment and remyelination were similar in PrP-deficient and wild-type mice. We conclude that PrP is dispensable for sciatic nerve de- and remyelination after crush injury. Adgrg6 may sustain its function in peripheral nerve repair independently of its activation by PrP.

Implication of Contactins in Demyelinating Pathologies.

Demyelinating pathologies comprise of a variety of conditions where either central or peripheral myelin is attacked, resulting in white matter lesions and neurodegeneration. Myelinated axons are organized into molecularly distinct domains, and this segregation is crucial for their proper function. These defined domains are differentially affected at the different stages of demyelination as well as at the lesion and perilesion sites. Among the main players in myelinated axon organization are proteins of the contactin (CNTN) group of the immunoglobulin superfamily (IgSF) of cell adhesion molecules, namely Contactin-1 and Contactin-2 (CNTN1, CNTN2). The two contactins perform their functions through intermolecular interactions, which are crucial for myelinated axon integrity and functionality. In this review, we focus on the implication of these two molecules as well as their interactors in demyelinating pathologies in humans. At first, we describe the organization and function of myelinated axons in the central (CNS) and the peripheral (PNS) nervous system, further analyzing the role of CNTN1 and CNTN2 as well as their interactors in myelination. In the last section, studies showing the correlation of the two contactins with demyelinating pathologies are reviewed, highlighting the importance of these recognition molecules in shaping the function of the nervous system in multiple ways.

Associations of cells from both innate and adaptive immunity with lower nerve conduction velocity: the Maastricht Study

IntroductionDistal sensorimotor polyneuropathy (DSPN) is common in people with diabetes but is also found in pre-diabetes. Peripheral nerve myelin damage, which can be assessed by reduced nerve conduction velocity (NCV),...

Определение уровня нейроспецифических аутоантител у больных Covid-19: предварительное сообщение

In severe COVID-19 patients the blood level of autoantibodies (IgG) to neurospecific proteins was determined. It defined the marked increase in autoantibodies to peripheral myelin protein, protein lipid protein, S100 protein, type 2 dopamine receptors and dopamine. At the same time, it was designate the relationship between the levels of autoantibodies to the S100 protein and NMDA receptors. High levels of specific IgG to SARS-CoV-2 S-Trimer Protein coincided with high levels of autoantibodies to S100 protein and NMDA receptors.

Glycosylation limits forward trafficking of the tetraspan membrane protein PMP22

Peripheral myelin protein 22 (PMP22) folds and trafficks inefficiently, with only 20% of newly expressed protein trafficking to the cell surface. This behavior is exacerbated in many of the mutants associated with Charcot–Marie–Tooth disease, motivating further study. Here we characterized the role of N-glycosylation in limiting PMP22 trafficking. We first eliminated N-glycosylation using an N41Q mutation, which resulted in an almost 3-fold increase in trafficking efficiency of wildtype (WT) PMP22 and a 10-fold increase for the severely unstable L16P disease mutant in HEK293 cells, with similar results in Schwann cells. Total cellular levels were also much higher for the WT/N41Q mutant, although not for the L16P/N41Q form. Depletion of oligosaccharyltransferase OST-A and OST-B subunits revealed that WT PMP22 is N-glycosylated posttranslationally by OST-B, whereas L16P is cotranslationally glycosylated by OST-A. Quantitative proteomic screens revealed similarities and differences in the interactome for WT, glycosylation-deficient, and unstable mutant forms of PMP22 and also suggested that L16P is sequestered at earlier stages of endoplasmic reticulum quality control. CRISPR knockout studies revealed a role for retention in endoplasmic reticulum sorting receptor 1 (RER1) in limiting the trafficking of all three forms, for UDP-glucose glycoprotein glucosyltransferase 1 (UGGT1) in limiting the trafficking of WT and L16P but not N41Q, and calnexin (CNX) in limiting the trafficking of WT and N41Q but not L16P. This work shows that N-glycosylation is a limiting factor to forward trafficking PMP22 and sheds light on the proteins involved in its quality control.

HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory.

Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning.

Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice.

The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the early molecular signs demyelination was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.

Engineering an Injectable Electroactive Nanohybrid Hydrogel for Boosting Peripheral Nerve Growth and Myelination in Combination with Electrical Stimulation.

Electrical stimulation (ES) can be used to manipulate recovery after peripheral nerve injuries. Although biomaterial-based strategies have already been implemented to gain momentum for ES and engineer permissive microenvironments for neural regeneration, the development of biomaterials for specific stimuli-responsive modulation of neural cell properties remains a challenge. Herein, we homogeneously incorporate pristine carbon nanotubes into a functional self-assembling peptide to prepare a hybrid hydrogel with good injectability and conductivity. Two-dimensional (on the surface) and three-dimensional (within the hybrid hydrogel) culturing experiments demonstrate that ES promotes axon outgrowth and Schwann cell (SC) migration away from dorsal root ganglia spheres, further revealing that ES-enhanced interactions between SCs and axons result in improved myelination. Thus, our study not only advances the development of tailor-made materials but also provides useful insights into comprehensive approaches for promoting nerve growth and presents a practical strategy of repairing peripheral nerve injuries.

Neuroimmune predictors of outcome after aneurysmal subarachnoid hemorrhage

Aim. To determine the possibility of predicting the course and outcomes of aneurysmal subarachnoid hemorrhage (aSAH) by using the detection of autoantibody level to neurospecific proteins.
 Methods. The autoantibody level to neurospecific proteins was detected in 65 people: 30 healthy volunteers and 35 with a confirmed diagnosis of aneurysmal subarachnoid hemorrhage. Autoantibodies to myelin basic protein (MBP), peripheral myelin, dopamine receptors, myosin, N-methyl-D-aspartate (NMDA) receptors and S100 protein detected by using an enzyme immunoassay. The severity of illness in dynamics was defined in all patients by using the following scales: Rivermead mobility index, HuntHess, Graeb and others. Statistical analysis was performed using Statistica 10.0, with the consistent use of descriptive statistics methods, the MannWhitney, KruskalWallis and Pearson tests, Spearman coefficient.
 Results. At the first stage, neurospecific proteins characterized by a large increase in autoantibody titers were identified. Further, based on the data obtained, a statistically significant correlation between autoantibody titers to S100 protein (360.4340.35 g/ml, p 0.05), MBP (145.9112.43 g/ml, p 0.05), NMDA receptors (66.176.42 g/ml, p 0.05) and aSAH outcome was established.
 Conclusion. The study revealed an increase in autoantibody level to neurospecific proteins in the blood plasma of patients, depending on the severity of subarachnoid hemorrhage and the development of delayed cerebral ischemia due to cerebral vasospasm; high antibodies titers to S100 protein in subarachnoid hemorrhage are associated with cerebral vasospasm and the development of secondary (delayed) ischemic changes in the brain.

Fibulin 5, a human Wharton's jelly-derived mesenchymal stem cells-secreted paracrine factor, attenuates peripheral nervous system myelination defects through the Integrin-RAC1 signaling axis.

In the peripheral nervous system (PNS), proper development of Schwann cells (SCs) contributing to axonal myelination is critical for neuronal function. Impairments of SCs or neuronal axons give rise to several myelin‐related disorders, including dysmyelinating and demyelinating diseases. Pathological mechanisms, however, have been understood at the elementary level and targeted therapeutics has remained undeveloped. Here, we identify Fibulin 5 (FBLN5), an extracellular matrix (ECM) protein, as a key paracrine factor of human Wharton's jelly‐derived mesenchymal stem cells (WJ‐MSCs) to control the development of SCs. We show that co‐culture with WJ‐MSCs or treatment of recombinant FBLN5 promotes the proliferation of SCs through ERK activation, whereas FBLN5‐depleted WJ‐MSCs do not. We further reveal that during myelination of SCs, FBLN5 binds to Integrin and modulates actin remodeling, such as the formation of lamellipodia and filopodia, through RAC1 activity. Finally, we show that FBLN5 effectively restores the myelination defects of SCs in the zebrafish model of Charcot‐Marie‐Tooth (CMT) type 1, a representative demyelinating disease. Overall, our data propose human WJ‐MSCs or FBLN5 protein as a potential treatment for myelin‐related diseases, including CMT.

Optic, trigeminal, and facial neuropathy related to anti-neurofascin 155 antibody.

ObjectiveTo characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti‐neurofascin 155 antibody‐positive (NF155+) chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsThirteen IgG4 NF155+ CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual‐evoked potential (VEP) testing, and axial and/or coronal T2‐weighted head magnetic resonance imaging (MRI).ResultsAmong 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti‐NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra‐orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration.InterpretationSubclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155+ CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers.

Phosphorylation of eIF2α Promotes Schwann Cell Differentiation and Myelination in CMT1B Mice with Activated UPR.

Myelin Protein Zero (MPZ/P0) is the most abundant glycoprotein of peripheral nerve myelin. P0 is synthesized by myelinating Schwann cells, processed in the endoplasmic reticulum (ER) and delivered to myelin via the secretory pathway. The mutant P0S63del (deletion of serine 63 in the extracellular domain of P0), that causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and a similar demyelinating neuropathy in transgenic mice, is instead retained the ER where it activates an unfolded protein response. Under ER-stress conditions, protein kinase R-like endoplasmic reticulum kinase (PERK) phosphorylates eukaryotic initiation factor 2α (eIF2α) to attenuate global translation, thus reducing the misfolded protein overload in the ER. Genetic and pharmacological inactivation of Gadd34 (damage-inducible protein 34), a subunit of the PP1 phosphatase complex that promotes the dephosphorylation of eIF2α, prolonged eIF2α phosphorylation and improved motor, neurophysiological, and morphologic deficits in S63del mice. However, PERK ablation in S63del Schwann cells ameliorated, rather than worsened, S63del neuropathy despite reduced levels of phosphorylated eIF2α. These contradictory findings prompted us to genetically explore the role of eIF2α phosphorylation in P0S63del-CMT1B neuropathy through the generation of mice in which eIF2α cannot be phosphorylated specifically in Schwann cells. Morphologic and electrophysiological analysis of male and female S63del mice showed a worsening of the neuropathy in the absence of eIF2α phosphorylation. However, we did not detect significant changes in ER stress levels, but rather a dramatic increase of the MEK/ERK/c-Jun pathway accompanied by a reduction in expression of myelin genes and a delay in Schwann cell differentiation. Our results support the hypothesis that eIF2α phosphorylation is protective in CMT1B and unveil a possible cross talk between eIF2α and the MEK/ERK pathway in neuropathic nerves.SIGNIFICANCE STATEMENT In the P0S63del (deletion of serine 63 in the extracellular domain of P0) mouse model of Charcot-Marie-Tooth type 1B (CMT1B), the genetic and pharmacological inhibition of Gadd34 (damage-inducible protein 34) prolonged eukaryotic initiation factor 2α (eIF2α) phosphorylation, leading to a proteostatic rebalance that significantly ameliorated the neuropathy. Yet, ablation of protein kinase R-like endoplasmic reticulum kinase (PERK) also ameliorated the S63del neuropathy, despite reduced levels of eIF2α phosphorylation (P-eIF2α). In this study, we provide genetic evidence that eIF2α phosphorylation has a protective role in CMT1B Schwann cells by limiting ERK/c-Jun hyperactivation. Our data support the targeting of the P-eIF2α/Gadd34 complex as a therapeutic avenue in CMT1B and also suggest that PERK may hamper myelination via mechanisms outside its role in the unfolded protein response.

Wide distribution of central myelin segment along the facial nerve might explain hemifacial spasm with distal nerve compression

Many researchers have assumed that neurovascular compression of the facial nerve at the site covered by central myelin sheath causes hemifacial spasm. However, some cases do not correspond to this hypothesis. The aim of this study was to clarify the myelin histology in the facial nerve. Histological analyses were conducted on 134 facial nerves from 67 cadavers. Three dimensions were measured in these sections: the length from the upper border of the medullopontine sulcus to the boundary between the central and peripheral myelin sheath along the anterior side; the length from the detachment point of the brain stem to the boundary along the posterior side; and the length of the transitional zone (TZ), known as the Obersteiner-Redlich zone. Of the 134 facial nerves, 41 were available for study. The length of the central myelin segment ranged from 4.62 to 12.6 mm (mean 8.06 mm; median 7.98 mm) along the anterior side and from 0.00 to 4.58 mm (mean 1.68 mm; median 1.42 mm) along the posterior side of the facial nerve, and the length of the TZ ranged from 0.00 to 2.76 mm (mean 1.51 mm; median 1.42 mm). In this study, the length of the central myelin segment in the facial nerve was found to be longer than that previously reported.

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A.

In Charcot–Marie–Tooth type 1A (CMT1A), Schwann cells exhibit a preponderant transcriptional deficiency of genes involved in lipid biosynthesis. This perturbed lipid metabolism affects the peripheral nerve physiology and the structure of peripheral myelin. Nevertheless, the identification and functional characterization of the lipid species mainly responsible for CMT1A myelin impairment currently lack. This is critical in the pathogenesis of the neuropathy since lipids are many and complex molecules which play essential roles in the cell, including the structural components of cellular membranes, cell signaling, and membrane trafficking. Moreover, lipids themselves are able to modify gene transcription, thereby affecting the genotype–phenotype correlation of well-defined inherited diseases, including CMT1A. Here we report for the first time a comprehensive lipid profiling in experimental and human CMT1A, demonstrating a previously unknown specific alteration of sphingolipid (SP) and glycerophospholipid (GP) metabolism. Notably, SP, and GP changes even emerge in biological fluids of CMT1A rat and human patients, implying a systemic metabolic dysfunction for these specific lipid classes. Actually, SP and GP are not merely reduced; their expression is instead aberrant, contributing to the ultrastructural abnormalities that we detailed by X-ray diffraction in rat and human internode myelin. The modulation of SP and GP pathways in myelinating dorsal root ganglia cultures clearly sustains this issue. In fact, just selected molecules interacting with these pathways are able to modify the altered geometric parameters of CMT1A myelinated fibers. Overall, we propose to exploit the present SP and GP metabolism impairment to select effective drugs and validate a set of reliable biomarkers, which remain a challenge in CMT1A neuropathy.

CTCF-mediated chromatin looping in EGR2 regulation and SUZ12 recruitment critical for peripheral myelination and repair

Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. In this report, we demonstrate that the CCCTC-binding factor (CTCF), a crucial chromatin organizer, is essential for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of CTCF or its deletion blocks Schwann cell differentiation at the pro-myelinating stage, whereas overexpression of CTCF promotes the myelination program. We find that CTCF establishes chromatin interaction loops between enhancer and promoter regulatory elements and promotes expression of a key pro-myelinogenic factor EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2 (PRC2), to repress the transcriptional program associated with negative regulation of Schwann cell maturation. Together, our findings reveal a dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block Schwann cell differentiation inhibitors to control peripheral myelination and repair.

Central nervous system impairment detected by somatosensory evoked potentials in patients with Charcot-Marie-Tooth disease type 1A

Diseases related to peripheral myelin protein 22 (PMP22) have been implicated to involve the central nervous system (CNS). This study aimed to detect central nerve impairment using somatosensory evoked potentials (SSEPs) in patients with Charcot-Marie-Tooth disease (CMT) 1A. A total of 30 CMT1A patients and 26 healthy volunteers were included. Baseline characteristics, brain MRI and segmental SSEPs were collected from the participants. The peak latencies of N9, N13 and N20 were recorded, and central conduction velocity (CCT) was calculated and compared between groups. Significant differences were found in the peak latencies and amplitudes of N9, N13 and N20 between the two groups. CCT was significantly prolonged in the CMT group (7.05 ± 2.09 ms) compared to the control group (5.40 ± 1.79 ms) (p = 0.003). Six of 30 CMT patients had abnormal MRI signals, but no correlation with CCT was found. The central somatosensory pathway that carries SSEPs was impaired in CMT1A patients, which implies an important underlying role of PMP22 in the CNS.

Motoneuron expression profiling identifies an association between an axonal splice variant of HDGF-related protein 3 and peripheral myelination

Disorders that disrupt myelin formation during development or in adulthood, such as multiple sclerosis and peripheral neuropathies, lead to severe pathologies, illustrating myelin's crucial role in normal neural functioning. However, although our understanding of glial biology is increasing, the signals that emanate from axons and regulate myelination remain largely unknown. To identify the core components of the myelination process, here we adopted a microarray analysis approach combined with laser-capture microdissection of spinal motoneurons during the myelinogenic phase of development. We identified neuronal genes whose expression was enriched during myelination and further investigated hepatoma-derived growth factor-related protein 3 (HRP3 or HDGFRP3). HRP3 was strongly expressed in the white matter fiber tracts of the peripheral (PNS) and central (CNS) nervous systems during myelination and remyelination in a cuprizone-induced demyelination model. The dynamic localization of HPR3 between axons and nuclei during myelination was consistent with its axonal localization during neuritogenesis. To study this phenomenon, we identified two splice variants encoded by the HRP3 gene: the canonical isoform HRP3-I and a newly recognized isoform, HRP3-II. HRP3-I remained solely in the nucleus, whereas HRP3-II displayed distinct axonal localization both before and during myelination. Interestingly, HRP3-II remained in the nuclei of unmyelinated neurons and glial cells, suggesting the existence of a molecular machinery that transfers it to and retains it in the axons of neurons fated for myelination. Overexpression of HRP3-II, but not of HRP3-I, increased Schwann cell numbers and myelination in PNS neuron-glia co-cultures. However, HRP3-II overexpression in CNS co-cultures did not alter myelination.