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.

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.

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

Normal role of the low‐molecular‐weight neurofilament protein in mitochondrial dynamics and disruption in Charcot‐Marie‐Tooth disease

2011 ◽  
Vol 26 (3) ◽  
pp. 1194-1203 ◽  
Author(s):  
Benoit J. Gentil ◽  
Sandra Minotti ◽  
Madeleine Beange ◽  
Robert H. Baloh ◽  
Jean‐Pierre Julien ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Mitochondrial Dynamics ◽  
Low Molecular Weight ◽  
Neurofilament Protein ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

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.

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