scholarly journals Farnesol Ameliorates Demyelinating Phenotype in a Cellular and Animal Model of Charcot-Marie-Tooth Disease Type 1A

2021 ◽  
Vol 43 (3) ◽  
pp. 2011-2021
Author(s):  
Na-Young Park ◽  
Geon Kwak ◽  
Hyun-Myung Doo ◽  
Hye-Jin Kim ◽  
So-Young Jang ◽  
...  
Keyword(s):  
Animal Model ◽  
Compound Muscle Action Potential ◽  
Motor Nerve ◽  
Motor Nerve Conduction Velocity ◽  
Causative Gene ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disease affecting the peripheral nervous system that is caused by either the demyelination of Schwann cells or degeneration of the peripheral axon. Currently, there are no treatment options to improve the degeneration of peripheral nerves in CMT patients. In this research, we assessed the potency of farnesol for improving the demyelinating phenotype using an animal model of CMT type 1A. In vitro treatment with farnesol facilitated myelin gene expression and ameliorated the myelination defect caused by PMP22 overexpression, the major causative gene in CMT. In vivo administration of farnesol enhanced the peripheral neuropathic phenotype, as shown by rotarod performance in a mouse model of CMT1A. Electrophysiologically, farnesol-administered CMT1A mice exhibited increased motor nerve conduction velocity and compound muscle action potential compared with control mice. The number and diameter of myelinated axons were also increased by farnesol treatment. The expression level of myelin protein zero (MPZ) was increased, while that of the demyelination marker, neural cell adhesion molecule (NCAM), was reduced by farnesol administration. These data imply that farnesol is efficacious in ameliorating the demyelinating phenotype of CMT, and further elucidation of the underlying mechanisms of farnesol’s effect on myelination might provide a potent therapeutic strategy for the demyelinating type of CMT.

scholarly journals An animal model for Charcot–Marie–Tooth disease type 4B1

2005 ◽  
Vol 14 (23) ◽  
pp. 3685-3695 ◽  
Author(s):  
Sonja Bonneick ◽  
Matthias Boentert ◽  
Philipp Berger ◽  
Suzana Atanasoski ◽  
Ned Mantei ◽  
...  
Keyword(s):  
Animal Model ◽  
Disease Type ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

In vitro models of Charcot-Marie-Tooth disease for investigating disease pathomechanisms

2017 ◽  
Vol 27 ◽  
pp. S27-S28
Author(s):  
V. Sarajarvi ◽  
B. Kalmar ◽  
M.M. Reilly ◽  
L. Greensmith
Keyword(s):  
In Vitro Models ◽  
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.

scholarly journals Motor Axonal Sprouting and Neuromuscular Junction Loss in an Animal Model of Charcot-Marie-Tooth Disease

2010 ◽  
Vol 69 (3) ◽  
pp. 281-293 ◽  
Author(s):  
Eng-Tat Ang ◽  
Ralf Schäfer ◽  
Richard Baltensperger ◽  
Anton Wernig ◽  
Marco Celio ◽  
...  
Keyword(s):  
Animal Model ◽  
Neuromuscular Junction ◽  
Axonal Sprouting ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals Analysis of compound muscle action potential in patients with chronic inflammatory demyelinating polyneuropathy and Charcot-Marie-Tooth disease type 1A

2021 ◽  
Vol 8 (2) ◽  
pp. 114-121
Author(s):  
Onur Akan ◽  
Canan Emir
Keyword(s):  
Peroneal Nerve ◽  
Tibial Nerve ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Compound Muscle Action Potential ◽  
Disease Type ◽  
Muscle Action ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Muscle Action Potential ◽  
Tooth Disease

Objective: To provide an additional contribution to the differential diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) and chronic inflammatory demyelinating polyneuropathy (CIDP)  by analyzing distal duration and proximal/distal amplitude and duration ratios on different nerves in these diseases that show demyelinating peripheral neuropathy features. Material and Methods: We retrospectively reviewed the electromyography (EMG) findings of patients aged 18-80 years who were followed up with a diagnosis of acquired and hereditary demyelinating type polyneuropathy in the neuromuscular diseases outpatient clinic in our center. We analyzed the distal CMAP duration and amplitude, proximal and distal compound muscle action potential, and duration ratios on each nerve in the patient groups, separately. Results: The CIDP group had significantly longer Peroneal nerve distal duration than the CMT1A group (p=0.04). Median, ulnar, and tibial nerve distal durations were similar between the groups (p=0.84, p=0.86, and p=0.13, respectively). The median nerve, ulnar nerve, and peroneal nerve proximal/distal amplitude ratios were not different between the CMT1A and CIDP groups (p=0.99, p=0.38, and p=0.16, respectively). The tibial nerve proximal/distal amplitude ratio in the CIDP group was lower than in the CMT1A group (p=0.003). Median, ulnar, peroneal, and tibial nerve proximal/distal duration ratios were statistically similar among the groups (p=0.21, p=0.66, p=0.62, and p=0.46, respectively). Conclusion: This study may help to improve the management of challenging patients where there is an overlap between hereditary and inflammatory neuropathies. The different electrodiagnostic models of various acquired and hereditary demyelinating polyneuropathies should be clinically recognized.

scholarly journals The Charcot Marie Tooth disease protein LITAF is a zinc-binding monotopic membrane protein

2016 ◽  
Vol 473 (21) ◽  
pp. 3965-3978 ◽  
Author(s):  
Wenxia Qin ◽  
Lydia Wunderley ◽  
Anne L. Barrett ◽  
Stephen High ◽  
Philip G. Woodman
Keyword(s):  
Membrane Protein ◽  
Multivesicular Body ◽  
Integral Membrane Protein ◽  
Membrane Topology ◽  
Zinc Binding ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease ◽  
In Cells

LITAF (LPS-induced TNF-activating factor) is an endosome-associated integral membrane protein important for multivesicular body sorting. Several mutations in LITAF cause autosomal-dominant Charcot Marie Tooth disease type 1C. These mutations map to a highly conserved C-terminal region, termed the LITAF domain, which includes a 22 residue hydrophobic sequence and flanking cysteine-rich regions that contain peptide motifs found in zinc fingers. Although the LITAF domain is thought to be responsible for membrane integration, the membrane topology of LITAF has not been established. Here, we have investigated whether LITAF is a tail-anchored (TA) membrane-spanning protein or monotopic membrane protein. When translated in vitro, LITAF integrates poorly into ER-derived microsomes compared with Sec61β, a bona fide TA protein. Furthermore, introduction of N-linked glycosylation reporters shows that neither the N-terminal nor C-terminal domains of LITAF translocate into the ER lumen. Expression in cells of an LITAF construct containing C-terminal glycosylation sites confirms that LITAF is not a TA protein in cells. Finally, an immunofluorescence-based latency assay showed that both the N- and C-termini of LITAF are exposed to the cytoplasm. Recombinant LITAF contains 1 mol/mol zinc, while mutation of predicted zinc-binding residues disrupts LITAF membrane association. Hence, we conclude that LITAF is a monotopic membrane protein whose membrane integration is stabilised by a zinc finger. The related human protein, CDIP1 (cell death involved p53 target 1), displays identical membrane topology, suggesting that this mode of membrane integration is conserved in LITAF family proteins.

scholarly journals Study of a Family with Progressive Ataxia, Tremor and Severe Distal Amyotrophy

1980 ◽  
Vol 7 (4) ◽  
pp. 345-349 ◽  
Author(s):  
J. Bouchard ◽  
P. Bedard ◽  
R. Bouchard
Keyword(s):  
Nerve Conduction ◽  
Motor Nerve ◽  
Elevated Serum ◽  
Sensory Nerve ◽  
Cerebellar Atrophy ◽  
Large Family ◽  
Charcot Marie Tooth ◽  
Progressive Development ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

SUMMARY:We have studied a large family of which seven members suffer from a progressive disease with onset in the first decade. The first symptoms were gait ataxia and clumsiness in all cases, followed by progressive development of severe distal amyotrophy reminiscent of Charcot-Marie-Tooth disease. In four patients a postural tremor which was relieved by pharmacological agents was also evident in the limbs or head.Cerebellar atrophy was confirmed on CT scan. Motor nerve conduction velocities were in the low normal range, while sensory nerve conduction was markedly decreased. All patients had impaired proprioception and vibration sense. The laboratory investigation revealed a normal CSF protein level and elevated serum bilirubin.The patients reported in this study apparently suffer from an original recessive form of spinal and olivocerebellar degeneration associated with a neuronal form of Charcot-Marie-Tooth disease.

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