Peripheral Nervous System Myelin Research Articles

A novel approach to 32-channel peripheral nervous system myelin imaging in vivo, with single axon resolution.

OBJECTIVE Intravital spectral imaging of the large, deeply situated nerves in the rat peripheral nervous system (PNS) has not been well described. Here, the authors have developed a highly stable platform for performing imaging of the tibial nerve in live rodents, thus allowing the capture of high-resolution, high-magnification spectral images requiring long acquisition times. By further exploiting the qualities of the topically applied myelin dye Nile red, this technique is capable of visualizing the detailed microenvironment of peripheral nerve demyelination injury and recovery, while allowing us to obtain images of exogenous Schwann cell myelination in a living animal. METHODS The authors caused doxorubicin-induced focal demyelination in the tibial nerves of 25 Thy-1 GFP rats, of which 2 subsets (n = 10 each) received either BFP-labeled SKP-SCs or SCs to the zone of injury. Prior to acquiring images of myelin recovery in these nerves, a tibial nerve window was constructed using a silicone hemitube, a fast drying silicone polymer, and a small coverslip. This construct was then affixed to a 3D-printed nerve stage, which in turn was affixed to an external fixation/microscope stage device. Myelin visualization was facilitated by the topical application of Nile red. RESULTS The authors reliably demonstrated intravital peripheral nerve myelin imaging with micron-level resolution and magnification, and minimal movement artifact. The detailed microenvironment of nerve remyelination can be vividly observed, while exogenously applied Schwann cells and skin-derived precursor Schwann cells can be seen myelinating axons. CONCLUSIONS Topically applied Nile red enables intravital study of myelin in the living rat PNS. Furthermore, the use of a tibial nerve window facilitates stable intravital peripheral nerve imaging, making possible high-definition spectral imaging with long acquisition times.

Genome expression profiling predicts the molecular mechanism of peripheral myelination.

The present study aimed to explore the molecular mechanism of myelination in the peripheral nervous system (PNS) based on genome expression profiles. Microarray data (GSE60345) was acquired from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were integrated and subsequently subjected to pathway and term enrichment analysis. A protein-protein interaction network was constructed and the top 200 DEGs according to their degree value were further subjected to pathway enrichment analysis. A microRNA (miR)-target gene regulatory network was constructed to explore the role of miRs associated with PNS myelination. A total of 783 upregulated genes and 307 downregulated genes were identified. The upregulated DEGs were significantly enriched in the biological function of complement and coagulation cascades, cytokine-cytokine receptor interactions and cell adhesion molecules. Pathways significantly enriched by the downregulated DEGs included the cell cycle, oocyte meiosis and the p53 signaling pathway. In addition, the upregulated DEGs among the top 200 DEGs were significantly enriched in natural killer (NK) cell mediated cytotoxicity and the B cell receptor (BCR) signaling pathway, in which Fc γ receptor (FCGR), ras-related C3 botulinum toxin substrate 2 (RAC2) and 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase γ-2 (PLCG2) were involved. miR-339-5p, miR-10a-5p and miR-10b-5p were identified as having a high degree value and may regulate the target genes TOX high mobility group box family member 4 (Tox4), DNA repair protein XRCC2 (Xrcc2) and C5a anaphylatoxin chemotactic receptor C5a2 (C5ar2). NK cell mediated cytotoxicity and the BCR pathway may be involved in peripheral myelination by targeting FCGR, RAC2 and PLCG2. The downregulation of oocyte meiosis, the cell cycle and the cellular tumor antigen p53 signaling pathway suggests decreasing schwann cell proliferation following the initiation of myelination. miR-339-5p, miR-10a-5p and miR-10b-5p may play important roles in PNS myelination by regulating Tox4, Xrcc2 and C5ar2.

Implications of Schwann Cells Biomechanics and Mechanosensitivity for Peripheral Nervous System Physiology and Pathophysiology.

The presence of bones around the central nervous system (CNS) provides it with highly effective physiologically crucial mechanical protection. The peripheral nervous system (PNS), in contrast, lacks this barrier. Consequently, the long held belief is that the PNS is mechanically vulnerable. On the other hand, the PNS is exposed to a variety of physiological mechanical stresses during regular daily activities. This fact prompts us to question the dogma of PNS mechanical vulnerability. As a matter of fact, impaired mechanics of PNS nerves is associated with neuropathies with the liability to mechanical stresses paralleled by significant impairment of PNS physiological functions. Our recent biomechanical integrity investigations on nerve fibers from wild-type and neuropathic mice lend strong support in favor of natural mechanical protection of the PNS and demonstrate a key role of Schwann cells (SCs) therein. Moreover, recent works point out that SCs can sense mechanical properties of their microenvironment and the evidence is growing that SCs mechanosensitivity is important for PNS development and myelination. Hence, SCs exhibit mechanical strength necessary for PNS mechanoprotection as well as mechanosensitivity necessary for PNS development and myelination. This mini review reflects on the intriguing dual ability of SCs and implications for PNS physiology and pathophysiology.

Friedreich Ataxia: Developmental Failure of the Dorsal Root Entry Zone.

Dorsal root ganglia, dorsal roots (DR), and dorsal root entry zones (DREZ) are vulnerable to frataxin deficiency in Friedreich ataxia (FA). A previously unrecognized abnormality is the intrusion of astroglial tissue into DR. Segments of formalin-fixed upper lumbar spinal cord of 13 homozygous and 2 compound heterozygous FA patients were sectioned longitudinally to represent DREZ and stained for glial fibrillary acidic protein (GFAP), S100, vimentin, the central nervous system (CNS)-specific myelin protein proteolipid protein, the peripheral nervous system (PNS) myelin proteins PMP-22 and P0, and the Schwann cell proteins laminin, alpha-dystroglycan, and periaxin. Normal DREZ showed short, sharply demarcated, dome-like extensions of CNS tissue into DR. The Schwann cell-related proteins formed tight caps around these domes. In FA, GFAP-, S100-, and vimentin-reactive CNS tissue extended across DREZ and into DR over much longer distances by breaching the CNS-PNS barrier. The transition between PNS and CNS myelin proteins was disorganized. During development, neural-crest derived boundary cap cells provide guidance to dorsal root ganglia axons growing into the dorsal spinal cord and at the same time block the inappropriate intrusion of CNS glia into DR. It is likely that frataxin is required during a critical period of permissive (axons) and nonpermissive (astroglia) border-control.

Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury

Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury.

Deficiency of a membrane skeletal protein, 4.1G, results in myelin abnormalities in the peripheral nervous system.

We previously demonstrated that a membrane skeletal molecular complex, 4.1G-membrane palmitoylated protein 6 (MPP6)-cell adhesion molecule 4, is incorporated in Schwann cells in the peripheral nervous system (PNS). In this study, we evaluated motor activity and myelin ultrastructures in 4.1G-deficient (-/-) mice. When suspended by the tail, aged 4.1G-/- mice displayed spastic leg extension, especially after overwork. Motor-conduction velocity in 4.1G-/- mice was slower than that in wild-type mice. Using electron microscopy, 4.1G-/- mice exhibited myelin abnormalities: myelin was thicker in internodes, and attachment of myelin tips was distorted in some paranodes. In addition, we found a novel function of 4.1G for sorting a scaffold protein, Lin7, due to disappearance of the immunolocalization and reduction of the production of Lin7c and Lin7a in 4.1G-/- sciatic nerves, as well as the interaction of MPP6 and Lin7 with immunoprecipitation. Thus, we herein propose 4.1G functions as a signal for proper formation of myelin in PNS.

A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination.

X-linked adrenoleukodystrophy (ALD) is a devastating inherited neurodegenerative disease caused by defects in the ABCD1 gene and affecting peripheral and central nervous system myelin. ABCD1 encodes a peroxisomal transmembrane protein required for very long chain fatty acid (VLCFA) metabolism. We show that zebrafish (Danio rerio) Abcd1 is highly conserved at the amino acid level with human ABCD1, and during development is expressed in homologous regions including the central nervous system and adrenal glands. We used TALENs to generate five zebrafish abcd1 mutant allele lines introducing premature stop codons in exon 1, as well as obtained an abcd1 allele from the Zebrafish Mutation Project carrying a point mutation in a splice donor site. Similar to patients with ALD, zebrafish abcd1 mutants have elevated VLCFA levels. Interestingly, we found that CNS development of the abcd1 mutants is disrupted, with hypomyelination in the spinal cord, abnormal patterning and decreased numbers of oligodendrocytes, and increased cell death. By day of life five abcd1 mutants demonstrate impaired motor function, and overall survival to adulthood of heterozygous and homozygous mutants is decreased. Expression of human ABCD1 in oligodendrocytes rescued apoptosis in the abcd1 mutant. In summary, we have established a zebrafish model of ALD that recapitulates key features of human disease pathology and which reveals novel features of underlying disease pathogenesis.

GlcNAc6ST-1 regulates sulfation of N-glycans and myelination in the peripheral nervous system

Highly specialized glial cells wrap axons with a multilayered myelin membrane in vertebrates. Myelin serves essential roles in the functioning of the nervous system. Axonal degeneration is the major cause of permanent neurological disability in primary myelin diseases. Many glycoproteins have been identified in myelin, and a lack of one myelin glycoprotein results in abnormal myelin structures in many cases. However, the roles of glycans on myelin glycoproteins remain poorly understood. Here, we report that sulfated N-glycans are involved in peripheral nervous system (PNS) myelination. PNS myelin glycoproteins contain highly abundant sulfated N-glycans. Major sulfated N-glycans were identified in both porcine and mouse PNS myelin, demonstrating that the 6-O-sulfation of N-acetylglucosamine (GlcNAc-6-O-sulfation) is highly conserved in PNS myelin between these species. P0 protein, the most abundant glycoprotein in PNS myelin and mutations in which at the glycosylation site cause Charcot-Marie-Tooth neuropathy, has abundant GlcNAc-6-O-sulfated N-glycans. Mice deficient in N-acetylglucosamine-6-O-sulfotransferase-1 (GlcNAc6ST-1) failed to synthesize sulfated N-glycans and exhibited abnormal myelination and axonal degeneration in the PNS. Taken together, this study demonstrates that GlcNAc6ST-1 modulates PNS myelination and myelinated axonal survival through the GlcNAc-6-O-sulfation of N-glycans on glycoproteins. These findings may provide novel insights into the pathogenesis of peripheral neuropathy.

The role of p38alpha in Schwann cells in regulating peripheral nerve myelination and repair.

Myelination in the peripheral nervous system (PNS) is controlled by both positive and negative regulators within Schwann cells to ensure timely onset and correct myelin thickness for saltatory conduction by neurons. Transcription factors such as Sox10, octamer-binding transcription factor 6 (Oct6) and Krox20 form a positive regulatory network, whereas negative regulators such as cJun and Sox2 oppose myelination in Schwann cells. The role of the p38 MAPK pathway has been studied in PNS myelination, but its precise function remains unclear, with both positive and negative effects of p38 activity reported upon both myelination and processes of nerve repair. To clarify the role of p38 MAPK in the PNS, we have analysed mice with a Schwann cell-specific ablation of the major p38 isoform, p38alpha. In line with previous findings of an inhibitory role for p38 MAPK, we observe acceleration of post-natal myelination in p38alpha null nerves, a delay in myelin down-regulation following injury, together with a small increase in levels of re-myelination following injury. Finally we explored roles for p38alpha in controlling axonal regeneration and functional repair following PNS injury and observe that loss of p38alpha function in Schwann cells does not appear to affect these processes as previously reported. These studies therefore provide further proof for a role of p38 MAPK signalling in the control of myelination by Schwann cells in the PNS, but do not show an apparent role for signalling by this MAP kinase in Schwann cells controlling other elements of Wallerian degeneration and functional repair following injury. Cover Image for this issue: doi: 10.1111/jnc.13793.

AMPK Negatively Regulates Peripheral Myelination via Activation of c-Jun.

The process of Schwann cells (SCs) forming a sheath around axons is termed as myelination, which plays a pivotal role for proper physiological function in the peripheral nervous system (PNS). The molecular mechanisms regulating SC myelination in the PNS remain to be elucidated. Here, we show that AMP-activated protein kinase (AMPK) in sciatic nerves was gradually decreased during the PNS myelination process. Pharmacological interventions showed that activation of AMPK by AICAR attenuated myelin gene expression in SCs, whereas inhibition of AMPK by Compound C (ComC) or AMPKα1 knockdown stimulated myelin gene expression. Following experiments revealed that c-Jun, a negative modulator of PNS myelination, was activated by AMPK in SCs. The application of ComC in newborn rats markedly downregulated c-Jun expression in sciatic nerves. The lipid and protein synthesis in sciatic nerves was greatly potentiated by ComC. As a consequence, myelin gene expression in sciatic nerves, as well as myelin sheath thickness, were promoted in the ComC-treated rats. All together, our data identify that AMPK is an important negative regulator of Schwann cell myelination in the PNS, and this regulation role may rely on c-Jun activation.

56. Intracerebroventricular and Intravenous AAV Gene Therapy in Canine Globoid Cell Leukodystrophy

Globoid cell leukodystrophy (GLD), or Krabbe disease, results from a deficiency in the hydrolytic enzyme galactosylceramidase (GALC), which is responsible for degrading the central and peripheral nervous system (CNS, PNS) myelin lipids galactosylceramide and galactosylsphingosine (psychosine). Symptoms in infants include irritability and stiffness with disease progressing rapidly to a vegetative state and death typically resulting by 2 years of age. GLD is naturally occurring in dogs and signs include ataxia, tremors, pelvic limb paralysis, loss of hearing, and blindness, with disease progression warranting euthanasia at 15.9 ± 4.6 weeks. In GLD dogs, GALC concentrations are decreased in leukocytes, CSF, and tissues and psychosine concentrations are elevated in serum and CSF. Conduction velocities in peripheral nerves of GLD dogs are < 50% of normal and G-ratios of the sciatic nerve are significantly higher than normal. Brain stem auditory evoked response testing exhibits a loss of waveform integrity and increased central conduction time consistent with auditory system demyelination. MRI of the brain shows T2-weighted hyperintensity of the white matter, widened sulci, and enlarged ventricles and MRS identified decreases in N-acetylaspartate and increases in choline. Diffusion tensor imaging established decreased fractional anisotropy and increased radial diffusivity in multiple white matter tracts including the corpus callosum and posterior internal capsule. Histologically, GLD dogs revealed severe loss of myelin, a decrease in oligodendrocytes, astrogliosis, and microgliosis. Combination gene therapy has been evaluated in GLD affected dogs using AAVrh10 encoding canine GALC (AAVrh10-cGALC). Two GLD dogs received a low dose of AAVrh10-cGALC, 1.2E12, by combination intravenous (IV) and intracerebroventricular (ICV) injection routes and displayed a modest increase in survival to 17.9 and 22.1 weeks of age. Two additional GLD dogs were treated with an increased dose of AAVrh10-cGALC, 1.9E13, and survival was further increased to 30.3 and 43.1 weeks of age. Both low and high dose combination IV and ICV therapy delayed the onset of neurological signs and prevented the onset of tremors, one of the debilitating neurologic signs in untreated GLD dogs. High dose AAVrh10-cGALC, but not low dose, resulted in complete normalization of pelvic and thoracic limb NCV and near normal sensory NCV. Combination therapy of either dose had negligible effect on the auditory system, as treated animals showed little to no improvement in distance between waveform peaks or hearing threshold over untreated animals. After high dose treatment with AAVrh10-cGALC, GALC activity reached near normal levels in the cerebellum and sciatic nerve, with levels decreasing in more distal brain regions. GALC levels in the liver and heart were intermediate between affected untreated GLD and normal control dogs. Interestingly, the highest GALC activity was found in the quadriceps muscle. GLD dogs treated with high dose AAV had CSF psychosine concentrations lower than untreated and low dose AAV-treated GLD dogs, despite being substantially older. Efficacy of hematopoietic stem cell transplant (HSCT) alone and in combination with IV AAVrh10-cGALC is currently being evaluated in GLD dogs. Ongoing studies suggest that addition of IV infusion of AAVrh10-cGALC substantially increases survival as compared to HSCT alone.

Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold.

Microtubule-based kinesin motors have many cellular functions, including the transport of a variety of cargos. However, unconventional roles have recently emerged, and kinesins have also been reported to act as scaffolding proteins and signaling molecules. In this work, we further extend the notion of unconventional functions for kinesin motor proteins, and we propose that Kif13b kinesin acts as a signaling molecule regulating peripheral nervous system (PNS) and central nervous system (CNS) myelination. In this process, positive and negative signals must be tightly coordinated in time and space to orchestrate myelin biogenesis. Here, we report that in Schwann cells Kif13b positively regulates myelination by promoting p38γ mitogen-activated protein kinase (MAPK)-mediated phosphorylation and ubiquitination of Discs large 1 (Dlg1), a known brake on myelination, which downregulates the phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homolog (AKT) pathway. Interestingly, Kif13b also negatively regulates Dlg1 stability in oligodendrocytes, in which Dlg1, in contrast to Schwann cells, enhances AKT activation and promotes myelination. Thus, our data indicate that Kif13b is a negative regulator of CNS myelination. In summary, we propose a novel function for the Kif13b kinesin in glial cells as a key component of the PI3K/AKT signaling pathway, which controls myelination in both PNS and CNS.

Adenomatous polyposis coli regulates radial axonal sorting and myelination in the PNS.

The tumor suppressor protein adenomatous polyposis coli (APC) is multifunctional - it participates in the canonical Wnt/β-catenin signal transduction pathway as well as modulating cytoskeleton function. Although APC is expressed by Schwann cells, the role that it plays in these cells and in the myelination of the peripheral nervous system (PNS) is unknown. Therefore, we used the Cre-lox approach to generate a mouse model in which APC expression is specifically eliminated from Schwann cells. These mice display hindlimb weakness and impaired axonal conduction in sciatic nerves. Detailed morphological analyses revealed that APC loss delays radial axonal sorting and PNS myelination. Furthermore, APC loss delays Schwann cell differentiation in vivo, which correlates with persistent activation of the Wnt signaling pathway and results in perturbed extension of Schwann cell processes and disrupted lamellipodia formation. In addition, APC-deficient Schwann cells display a transient diminution of proliferative capacity. Our data indicate that APC is required by Schwann cells for their timely differentiation to mature, myelinating cells and plays a crucial role in radial axonal sorting and PNS myelination.

Aging-associated changes in motor axon voltage-gated Na+ channel function in mice

Accumulating myelin abnormalities and conduction slowing occur in peripheral nerves during aging. In mice deficient of myelin protein P0, severe peripheral nervous system myelin damage is associated with ectopic expression of Nav1.8 voltage-gated Na+ channels on motor axons aggravating the functional impairment. The aim of the present study was to investigate the effect of regular aging on motor axon function with particular emphasis on Nav1.8. We compared tibial nerve conduction and excitability measures by threshold tracking in 12 months (mature) and 20 months (aged) wild-type (WT) mice. With aging, deviations during threshold electrotonus were attenuated and the resting current-threshold slope and early refractoriness were increased. Modeling indicated that, in addition to changes in passive membrane properties, motor fibers in aged WT mice were depolarized. An increased Nav1.8 isoform expression was found by immunohistochemistry. The depolarizing excitability features were absent in Nav1.8 null mice, and they were counteracted in WT mice by a Nav1.8 blocker. Our data suggest that alteration in voltage-gated Na+ channel isoform expression contributes to changes in motor axon function during aging.

Neuronal ADAM10 Promotes Outgrowth of Small-Caliber Myelinated Axons in the Peripheral Nervous System.

The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases.

Production, crystallization and neutron diffraction of fully deuterated human myelin peripheral membrane protein P2.

The molecular details of the formation of the myelin sheath, a multilayered membrane in the nervous system, are to a large extent unknown. P2 is a peripheral membrane protein from peripheral nervous system myelin, which is believed to play a role in this process. X-ray crystallographic studies and complementary experiments have provided information on the structure-function relationships in P2. In this study, a fully deuterated sample of human P2 was produced. Crystals that were large enough for neutron diffraction were grown by a ten-month procedure of feeding, and neutron diffraction data were collected to a resolution of 2.4 Å from a crystal of 0.09 mm(3) in volume. The neutron crystal structure will allow the positions of H atoms in P2 and its fatty-acid ligand to be visualized, as well as shedding light on the fine details of the hydrogen-bonding networks within the P2 ligand-binding cavity.

The Lin28/let-7 axis is critical for myelination in the peripheral nervous system.

MicroRNAs (miRNAs) are crucial regulators of myelination in the peripheral nervous system (PNS). However, the miRNAs species involved and the underlying mechanisms are largely unknown. We found that let-7 miRNAs are highly abundant during PNS myelination and that their levels are inversely correlated to the expression of lin28 homolog B (Lin28B), an antagonist of let-7 accumulation. Sustained expression of Lin28B and consequently reduced levels of let-7 miRNAs results in a failure of Schwann cell myelination in transgenic mouse models and in cell culture. Subsequent analyses revealed that let-7 miRNAs promote expression of the myelination-driving master transcription factor Krox20 (also known as Egr2) through suppression of myelination inhibitory Notch signalling. We conclude that the Lin28B/let-7 axis acts as a critical driver of PNS myelination, in particular by regulating myelination onset, identifying this pathway also as a potential therapeutic target in demyelinating diseases.

Gamma Knife Stereotactic Radiosurgery (GKS) for the treatment of Vestibular Schwannomas (VS)

Introduction. Vestibular schwannomas (VS) or acoustic neuromas (AN) (as they are known to neurosurgeons) are benign tumors which originate at the junction between central nervous system myelin and peripheral nervous system myelin – an area known as the Obersteiner-Redlich area. Acoustic neuromas represent a special pathologic entity for neurosurgeons due to their important symptoms which need to be adressed as soon as possible and due to the secondary disfunctions which may appear if the tumors are not treated appropriately. Materials and methods. The study below presents the experience of the authors regarding the use of stereotactic radiosurgery for the treatment of acoustic neuromas. The authors focus on a population of 231 patients diagnosed and treated for VS over a period of 10 years at the „Bagdasar-Arseni“ University Hospital in Bucharest. This study compares the impact of Gamma Knife Surgery when performed alone or in association with open microneurosurgery. The authors assessed patients with tumors ranging between 0.25 and 14 cm3 in volume. Gamma Knife Surgery is used successfully to treat VS, both independantly or in association with open microsurgery. Results. The major complications of the treatment are represented by lack of response to treatment (less than 1% of patients) and cerebral edema (16.4% of patients). Conclusions. Given its multiple advantages, stereotactic radiosurgery is right now the tip of the spear regarding the therapeutical means available for VS. When the tumors met in daily practice are larger than the therapeutical resources of the devices used for Gamma Knife Surgery an open microsurgical approach may be attempted followed by stereotactic iradiation of the remnant tumor. Given the large number of successes reported in the literature and the small number of complications but also the ever progressing technology used to improve Gamma Knife devices, the authors consider stereotactic radiosurgery to be a very good solution for the treatment of VS. Furthermore, the improvement potential this technique has grants it the potential to improve standard of treatment for acoustic neuromas and the quality of life in patients with this disease.

Resequencing of early growth response 2 (EGR2) gene revealed a recurrent patient-specific mutation in schizophrenia

Abnormal myelination is considered as part of the pathophysiology of schizophrenia. We resequenced the genomic DNA of the EGR2, which has a specific function in the myelination of peripheral nervous system, in 543 schizophrenic patients and 554 non-psychotic controls. We identified six known SNPs, which were not associated with schizophrenia. Nevertheless, we discovered 24 rare mutations, some of them were patient-specific, including a recurrent mutation (p.P173_Y174insP), which might be associated with the pathogenesis of schizophrenia.

Sox4 participates in the modulation of Schwann cell myelination.

In order to identify new regulators of Schwann cell myelination potentially playing a role in peripheral nervous system (PNS) pathologies, we analysed gene expression profiling data from three mouse models of demyelinating neuropathies and from the developing PNS. This analysis revealed that Sox4, which encodes a member of the Sry-related high-mobility group box protein family, was consistently upregulated in all three analysed models of neuropathy. Moreover, Sox4 showed a peak in its expression during development that corresponded with the onset of myelination. To gain further insights into the role of Sox4 in PNS development, we generated a transgenic mouse that specifically overexpresses Sox4 in Schwann cells. Sox4 overexpression led to a temporary delay in PNS myelination without affecting axonal sorting. Importantly, we observed that, whereas Sox4 mRNA could be efficiently overexpressed, Sox4 protein expression in Schwann cells was strictly regulated. Finally, our data showed that enforced expression of Sox4 in the mouse model for Charcot-Marie-Tooth 4C aggravated its neuropathic phenotype. Together, these observations reveal that Sox4 contributes to the regulation of Schwann cell myelination, and also indicates its involvement in the pathophysiology of peripheral neuropathies.