A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases (original) (raw)
Related papers
2020
Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth (CMT) diseases, that are commonly associated with a process of demyelination. Peripheral neuropathy is a major complication of diabetes, and the pathomechanism of the disease remains poorly studied. Here, we studied the progressive demyelinating process, hearing impairment and blindness observed in the CMT1A mouse model C3. Our results confirm that these mice represent a robust and validated model to study the peripheral neuropathy induced by CMT disorder allowing to determine the efficacy of new pharmacological candidates targeting demyelinating diseases such as CMT1A disorder.
Animal models of Charcot-Marie-Tooth disease type 1A
NeuroMolecular Medicine, 2006
The most frequent genetic subtype of Charcot-Marie-Tooth disease is CMT1A, linked to chromosome 17p11.2. In the majority of cases, CMT1A is a gene dosage disease associated with a 1.5 Mb large genomic duplication. Transgenic models with extra copies of the Pmp22 gene have provided formal proof that overexpression of only this candidate gene is sufficent to cause peripheral demyelination, onion bulb formation, secondary axonal loss, and progressive muscle atrophy, the pathological hallmarks of CMT1A. The transgenic CMT rat with about 1.6-fold PMP22 overexpression exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimick findings in CMT1A patients. Also transgenic mice, carrying yeast artifical chromosomes as Pmp22 transgenes, demonstrate the variability of disease expression as a function of increased gene dosage. Recently, the first rational experimental therapies of CMT1A were tested, using transgenic animal models. In one proof-of-principle study with the CMT rat, a synthetic antagonist of the nuclear progesterone receptor was shown to reduce PMP22 overexpression and to ameliorate the clinical severity. In another study, administration of ascorbic acid, an essential factor of in vitro myelination, prolonged the survival and restored myelination of a dysmyelinated mouse model. Application of gene expression analysis to nerve biopsies that are readily available from such CMT1A animal models might identify additional pharmacological targets.
Reversal of neuropathy phenotypes in conditional mouse model of Charcot-Marie-Tooth disease type 2E
Human Molecular Genetics, 2010
Mutations in the gene encoding for the neurofilament light subunit (NF-L) are responsible for Charcot -Marie -Tooth (CMT) neuropathy type 2E. To address whether CMT2E disease is potentially reversible, we generated a mouse model with conditional doxycycline-responsive gene system that allows repression of mutant hNF-L P22S transgene expression in adult neurons. The hNF-L P22S ;tTa transgenic (tg) mice recapitulated key features of CMT2E disease, including aberrant hindlimb posture, motor deficits, hypertrophy of muscle fibres and loss of muscle innervation without neuronal loss. Remarkably, a 3-month treatment of hNF-L P22S ;tTa mice with doxycycline after onset of disease efficiently down-regulated expression of hNF-L P22S and it caused reversal of CMT neurological phenotypes with restoration of muscle innervation and of neurofilament protein distribution along the sciatic nerve. These data suggest that therapeutic approaches aimed at abolishing expression or neutralizing hNF-L mutants might not only halt the progress of CMT2E disease, but also revert the disabilities.
A transgenic rat model of Charcot-Marie-Tooth disease
Neuron, 1996
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy in humans and has been associated with a partial duplication of chromosome 17 (CMT type 1A). We have generated a transgenic rat model of this disease and provide experimental evidence that CMT1A is ...
Charcot-Marie-Tooth disease: Emerging mechanisms and therapies
The International Journal of Biochemistry & Cell Biology, 2012
Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system. The disease is characterized by a progressive muscle weakness and atrophy, sensory loss, foot (and hand) deformities and steppage gait. While many of the genes associated with axonal CMT have been identified, to date it is unknown which mechanism(s) causes the disease. However, genetic findings indicate that the underlying mechanisms mainly converge to the axonal cytoskeleton. In this review, we will summarize the evidence for this pathogenic convergence. Furthermore, recent work with new transgenic mouse models has led to the identification of histone deacetylase 6 as a potential therapeutic target for inherited peripheral neuropathies. This enzyme deacetylates microtubules and plays a crucial role in the regulation of axonal transport. These findings offer new perspectives for a potential therapy to treat axonal Charcot-Marie-Tooth disease and other neurodegenerative disorders characterized by axonal transport defects.
Brain Research, 2019
Charcot-Marie-Tooth (CMT) disease is a progressive and heterogeneous inherited peripheral neuropathy. A myriad of genetic factors have been identified that contribute to the degeneration of motor and sensory axons in a length-dependent manner. Emerging biological themes underlying disease include defects in axonal trafficking, dysfunction in RNA metabolism and protein homeostasis, as well deficits in the cellular stress response. Moreover, genetic contributions to CMT can have overlap with other neuropathies, motor neuron diseases (MNDs) and neurodegenerative disorders. Recent progress in understanding the molecular biology of CMT and overlapping syndromes aids in the search for necessary therapeutic targets.
Neurobiology of Disease, 2000
The First Workshop of the European Consortium on Charcot-Marie-Tooth (CMT) disease brought together neuroscientists, molecular and cell biologists, neuropathologists, neurologists, and geneti cists with a common interest in the understanding of the fundamental mechanisms that underlie the pathogenesis of CMT. The interdisciplinary group of 25 expert scientists discussed recent advances in (i) molecular genetics and histopathology of CMT, (ii) development of suitable animal models, (rii) understanding of the cellular function of CMT-related proteins, and (iv) studies using nerve biopsies from CMT patients. In this minireview, we summarize the key findings presented and discuss their impact on CMT research.
Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies
International Journal of Molecular Sciences, 2021
Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropria...
Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success
Genes, 2014
Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. Genetic research of CMT has pioneered the discovery of genomic disorders and aided in understanding the effects of copy number variation and the mechanisms of genomic rearrangements. CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. The reference genome, which became available thanks to the Human Genome Project, and the development of next generation sequencing tools, considerably accelerated gene and mutation discoveries. In fact, the first clinical whole genome sequence was reported in a patient with CMT. Here we review the history of CMT gene discoveries, starting with technologies from the early days in human genetics through the high-throughput application of modern DNA analyses. We highlight the most relevant examples of CMT genes and mutation mechanisms, some of which provide promising treatment strategies. Finally, we propose future initiatives to accelerate