scholarly journals Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination

2019 ◽  
Author(s):  
Anna E. Mammel ◽  
Katherine C. Delgado ◽  
Andrea L. Chin ◽  
Alec F. Condon ◽  
Jo Q. Hill ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Protein Complexes ◽  
Endosomal Trafficking ◽  
Rab Gtpases ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Type ◽  
Perinatal Lethality ◽  
Radial Sorting ◽  
Redundant Functions

ABSTRACTThe form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET Binding Factor 1; SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS). MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2. In the mouse PNS, Mtmr2 was required to maintain wild type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 in mice led to perinatal lethality, indicating that the two proteins have partially redundant functions during embryogenesis. Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects. Mtmr5 levels were highest during axon radial sorting, whereas Mtmr13 levels rose as myelin formed, and remained high through adulthood. Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2. This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease.

scholarly journals An In Vitro Model of Charcot-Marie-Tooth Disease Type 4B2 Provides Insight Into the Roles of MTMR13 and MTMR2 in Schwann Cell Myelination

ASN NEURO ◽  
2018 ◽  
Vol 10 ◽  
pp. 175909141880328 ◽  
Author(s):  
Danielle C. Robinson ◽  
Anna E. Mammel ◽  
Anne M. Logan ◽  
Aubree A. Larson ◽  
Eric J. Schmidt ◽  
...  
Keyword(s):  
Schwann Cell ◽  
In Vitro Model ◽  
Endosomal Trafficking ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Vitro Model ◽  
Demyelinating Peripheral Neuropathy ◽  
Vacuolar Protein

Charcot-Marie-Tooth Disorder Type 4B (CMT4B) is a demyelinating peripheral neuropathy caused by mutations in myotubularin-related (MTMR) proteins 2, 13, or 5 (CMT4B1/2/3), which regulate phosphoinositide turnover and endosomal trafficking. Although mouse models of CMT4B2 exist, an in vitro model would make possible pharmacological and reverse genetic experiments needed to clarify the role of MTMR13 in myelination. We have generated such a model using Schwann cell-dorsal root ganglion (SC-DRG) explants from Mtmr13−/− mice. Myelin sheaths in mutant cultures contain outfoldings highly reminiscent of those observed in the nerves of Mtmr13−/− mice and CMT4B2 patients. Mtmr13−/− SC-DRG explants also contain reduced Mtmr2, further supporting a role of Mtmr13 in stabilizing Mtmr2. Elevated PI(3,5)P2 has been implicated as a cause of myelin outfoldings in Mtmr2−/− models. In contrast, the role of elevated PI3P or PI(3,5)P2 in promoting outfoldings in Mtmr13−/− models is unclear. We found that over-expression of MTMR2 in Mtmr13−/− SC-DRGs moderately reduced the prevalence of myelin outfoldings. Thus, a manipulation predicted to lower PI3P and PI(3,5)P2 partially suppressed the phenotype caused by Mtmr13 deficiency. We also explored the relationship between CMT4B2-like myelin outfoldings and kinases that produce PI3P and PI(3,5)P2 by analyzing nerve pathology in mice lacking both Mtmr13 and one of two specific PI 3-kinases. Intriguingly, the loss of vacuolar protein sorting 34 or PI3K-C2β in Mtmr13−/− mice had no impact on the prevalence of myelin outfoldings. In aggregate, our findings suggest that the MTMR13 scaffold protein likely has critical functions other than stabilizing MTMR2 to achieve an adequate level of PI 3-phosphatase activity.

scholarly journals A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

2018 ◽  
Vol 3 ◽  
pp. 20 ◽  
Author(s):  
Diane L. Sherman ◽  
Peter J. Brophy
Keyword(s):  
Plasma Membrane ◽  
Schwann Cell ◽  
Laminin Receptor ◽  
Cell Plasma Membrane ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
C Terminus ◽  
Cell Plasma ◽  
Inherited Neuropathies ◽  
Tooth Disease

Charcot-Marie-Tooth (CMT) disease comprises up to 80 monogenic inherited neuropathies of the peripheral nervous system (PNS) that collectively result in demyelination and axon degeneration. The majority of CMT disease is primarily either dysmyelinating or demyelinating in which mutations affect the ability of Schwann cells to either assemble or stabilize peripheral nerve myelin. CMT4F is a recessive demyelinating form of the disease caused by mutations in the Periaxin (PRX) gene. Periaxin (Prx) interacts with Dystrophin Related Protein 2 (Drp2) in an adhesion complex with the laminin receptor Dystroglycan (Dag). In mice the Prx/Drp2/Dag complex assembles adhesive domains at the interface between the abaxonal surface of the myelin sheath and the cytoplasmic surface of the Schwann cell plasma membrane. Assembly of these appositions causes the formation of cytoplasmic channels called Cajal bands beneath the surface of the Schwann cell plasma membrane. Loss of either Periaxin or Drp2 disrupts the appositions and causes CMT in both mouse and man. In a mouse model of CMT4F, complete loss of Periaxin first prevents normal Schwann cell elongation resulting in abnormally short internodal distances which can reduce nerve conduction velocity, and subsequently precipitates demyelination. Distinct functional domains responsible for Periaxin homodimerization and interaction with Drp2 to form the Prx/Drp2/Dag complex have been identified at the N-terminus of Periaxin. However, CMT4F can also be caused by a mutation that results in the truncation of Periaxin at the extreme C-terminus with the loss of 391 amino acids. By modelling this in mice, we show that loss of the C-terminus of Periaxin results in a surprising reduction in Drp2. This would be predicted to cause the observed instability of both appositions and myelin, and contribute significantly to the clinical phenotype in CMT4F.

Charcot–Marie–Tooth type 4B demyelinating neuropathy: deciphering the role of MTMR phosphatases

2007 ◽  
Vol 9 (25) ◽  
pp. 1-16 ◽  
Author(s):  
Stefano C. Previtali ◽  
Angelo Quattrini ◽  
Alessandra Bolino
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Autosomal Recessive ◽  
Protein Tyrosine Phosphatases ◽  
Vesicular Trafficking ◽  
Demyelinating Neuropathy ◽  
Charcot Marie Tooth ◽  
Catalytically Active ◽  
Tooth Type

AbstractCharcot–Marie–Tooth type 4B (CMT4B) is a severe autosomal recessive neuropathy with demyelination and myelin outfoldings of the nerve. This disorder is genetically heterogeneous, but thus far, mutations in myotubularin-related 2 (MTMR2) and MTMR13 genes have been shown to underlie CMT4B1 and CMT4B2, respectively. MTMR2 and MTMR13 belong to a family of ubiquitously expressed proteins sharing homology with protein tyrosine phosphatases (PTPs). The MTMR family, which has 14 members in humans, comprises catalytically active proteins, such as MTMR2, and catalytically inactive proteins, such as MTMR13. Despite their homology with PTPs, catalytically active MTMR phosphatases dephosphorylate both PtdIns3P and PtdIns(3,5)P2 phosphoinositides. Thus, MTMR2 and MTMR13 may regulate vesicular trafficking in Schwann cells. Loss of these proteins could lead to uncontrolled folding of myelin and, ultimately, to CMT4B. In this review, we discuss recent findings on this interesting protein family with the main focus on MTMR2 and MTMR13 and their involvement in the biology of Schwann cell and CMT4B neuropathies.

scholarly journals Nonmyelinating Schwann Cell Involvement With Well-Preserved Unmyelinated Axons in Charcot-Marie-Tooth Disease Type 1A

2007 ◽  
Vol 66 (11) ◽  
pp. 1027-1036 ◽  
Author(s):  
Haruki Koike ◽  
Masahiro Iijima ◽  
Keiko Mori ◽  
Masahiko Yamamoto ◽  
Naoki Hattori ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Disease Type ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Unmyelinated Axons ◽  
Tooth Disease

scholarly journals Neural and Molecular Features on Charcot-Marie-Tooth Disease Plasticity and Therapy

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Paula Juárez ◽  
Francesc Palau
Keyword(s):  
Schwann Cell ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Sensory Nerves ◽  
Peripheral Neuropathies ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Molecular Features ◽  
Tooth Disease

In the peripheral nervous system disorders plasticity is related to changes on the axon and Schwann cell biology, and the synaptic formations and connections, which could be also a focus for therapeutic research. Charcot-Marie-Tooth disease (CMT) represents a large group of inherited peripheral neuropathies that involve mainly both motor and sensory nerves and induce muscular atrophy and weakness. Genetic analysis has identified several pathways and molecular mechanisms involving myelin structure and proper nerve myelination, transcriptional regulation, protein turnover, vesicle trafficking, axonal transport and mitochondrial dynamics. These pathogenic mechanisms affect the continuous signaling and dialogue between the Schwann cell and the axon, having as final result the loss of myelin and nerve maintenance; however, some late onset axonal CMT neuropathies are a consequence of Schwann cell specific changes not affecting myelin. Comprehension of molecular pathways involved in Schwann cell-axonal interactions is likely not only to increase the understanding of nerve biology but also to identify the molecular targets and cell pathways to design novel therapeutic approaches for inherited neuropathies but also for most common peripheral neuropathies. These approaches should improve the plasticity of the synaptic connections at the neuromuscular junction and regenerate cell viability based on improving myelin and axon interaction.

Detection of Charcot-Marie-Tooth type 1A duplication by the polymerase chain reaction

1995 ◽  
Vol 41 (8) ◽  
pp. 1105-1108 ◽  
Author(s):  
I P Blair ◽  
M L Kennerson ◽  
G A Nicholson
Keyword(s):  
Polymerase Chain Reaction ◽  
Genetic Locus ◽  
Chain Reaction ◽  
Peripheral Myelin Protein ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Type ◽  
Polymerase Chain ◽  
Hereditary Peripheral Neuropathy ◽  
Tooth Disease

Abstract Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy with a genetic locus on chromosome 17p11.2. The majority of patients carry a duplicated DNA segment that encompasses the gene PMP22, which encodes a peripheral myelin protein. PMP22 is the crucial gene involved in the pathogenesis of CMT1A. Molecular diagnosis of CMT1A requires detection of this duplicated segment. Existing methods for detection of the duplication are laborious and time consuming. We have developed a set of polymorphic (AC)n repeat markers (contained within the duplication) for use in the polymerase chain reaction, which give a high probability of detecting three unique alleles in affected individuals. This test detected 85% of a panel of 52 CMT1A patients in which the duplication had previously been demonstrated.

MicroRNAs as Biomarkers of Charcot-Marie-Tooth Disease Type 1A

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012266
Author(s):  
Hongge Wang ◽  
Matthew Davison ◽  
Kathryn Wang ◽  
Tai-he Xia ◽  
Katherine M. Call ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Motor Nerve ◽  
Disease Type ◽  
Class Iii ◽  
Protein Biomarkers ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Compound Muscle Action Potentials ◽  
Tooth Disease

Objective:To determine if microRNA’s (miR) are elevated in the plasma of individuals affected by the inherited peripheral neuropathy Charcot-Marie-Tooth Disease, type 1A (CMT1A), miR profiling was employed to compare control and CMT1A plasma.Methods:We performed a screen of CMT1A and control plasma samples to identify miRs that are elevated in CMT1A using next generation sequencing, followed by validation of selected miRs by quantitative PCR, and correlation with protein biomarkers and clinical data: Rash-modified CMT Examination and Neuropathy Scores (CMTES-R and CMTNS-R), ulnar compound muscle action potentials (CMAP), and motor nerve conduction velocities (MNCV).Results:After an initial pilot screen, a broader screen confirmed elevated levels of several muscle-associated miRNAs (miR1, -133a, -133b, and -206, known as myomiRs) along with a set of miRs that are highly expressed in Schwann cells of peripheral nerve. Comparison to other candidate biomarkers for CMT1A (e.g. Neurofilament L, NfL) measured on the same sample set shows a comparable elevation of several miRs (e.g. miR133a, -206, -223) and ability to discriminate cases from controls. NfL levels were most highly correlated with miR133a. In addition, the putative Schwann cell miRs (e.g. miR223, -199a, -328, -409, and -431) correlate with the recently described TMPRSS5 protein biomarker that is most highly expressed in Schwann cells and also elevated in CMT1A plasma.Conclusions:These studies identify a set of miRs that are candidate biomarkers for clinical trials in CMT1A. Some of the miRs may reflect Schwann cell processes that underlie the pathogenesis of the disease.Classification of Evidence:This study provides Class III evidence that a set of plasma miRs are elevated in patients with CMT1A.

scholarly journals Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

2015 ◽  
Vol 35 (14) ◽  
pp. 2464-2478 ◽  
Author(s):  
Wenjing Li ◽  
Hong Zhu ◽  
Xuelian Zhao ◽  
Deborah Brancho ◽  
Yuanxin Liang ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Signal Propagation ◽  
Transforming Growth Factor Β ◽  
Receptor Activation ◽  
Nuclear Accumulation ◽  
Endosomal Trafficking ◽  
Inflammatory Signaling ◽  
Charcot Marie Tooth ◽  
Late Endosomes ◽  
Tooth Type

Endosomal trafficking is a key mechanism to modulate signal propagation and cross talk. Ubiquitin adaptors, along withendosomalsortingcomplexrequired fortransport (ESCRT) complexes, are also integrated to terminate ligand-receptor activation in late endosomes and multivesicular bodies (MVBs). Within these pathways, we recently demonstrated that the protein SIMPLE is a novel player in MVB regulation. SIMPLE is also clinically important and its mutation accounts for the Charcot-Marie-Tooth type 1C (CMT1C) disease. MVB defects of mutation and deletion of SIMPLE, however, are distinct. Here, we show that MVB defects found in mutation but not deletion of SIMPLE lead to impaired turnover and accumulation of ESCRT-0 protein Hrs puncta in late endosomes. We further uncover increased colocalization of ubiquitin ligase TRAF6 and Hrs in late endosomes. Upon stimulation with interkeukin-1 or transforming growth factor β, prolonged activation of p38 kinase/JNK is detected, while nuclear accumulation of NF-κB and phosphorylation of SMAD2 is reduced with CMT1C mutation. The aberrant kinetics we observed in inflammatory signaling may contribute to increased tumor susceptibility and changes in the levels of chemokines/cytokines that result from CMT1C mutation. We propose that altered endosomal trafficking due to malformations of MVBs and subsequent atypical signaling kinetic may account for a toxic gain of function in CMT1C pathogenesis.

scholarly journals Direct binding of the flexible C-terminal segment of periaxin to β4 integrin suggests a molecular basis for CMT4F

2019 ◽  
Author(s):  
Arne Raasakka ◽  
Helen Linxweiler ◽  
Peter J Brophy ◽  
Diane L Sherman ◽  
Petri Kursula
Keyword(s):  
Schwann Cell ◽  
Basal Lamina ◽  
Protein Complexes ◽  
Terminal Segment ◽  
Terminal Region ◽  
Membrane Receptors ◽  
Charcot Marie Tooth Disease ◽  
Cell Cytoskeleton ◽  
C Terminus ◽  
Β4 Integrin

The process of myelination in the nervous system requires coordinated formation of both transient and stable supramolecular complexes. Myelin-specific proteins play key roles in these assemblies, which may link membranes to each other or connect the myelinating cell cytoskeleton to the extracellular matrix. The myelin protein periaxin is known to play an important role in linking the Schwann cell cytoskeleton to the basal lamina through membrane receptors, such as the dystroglycan complex. Mutations that truncate periaxin from the C terminus cause demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 4F, indicating a function for the periaxin C-terminal region in myelination. We identified the cytoplasmic domain of β4 integrin as a specific high-affinity binding partner for periaxin. The C-terminal region of periaxin remains unfolded and flexible when bound to the third fibronectin type III domain of β4 integrin. Our data suggest that periaxin is able to link the Schwann cell cytoplasm to the basal lamina through a two-pronged interaction via different membrane protein complexes, which bind close to the N and C terminus of this elongated, flexible molecule.

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