scholarly journals Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

2021 ◽  
Author(s):  
Yingli Gu ◽  
Flora Guerra ◽  
Mingzheng Hu ◽  
Alexander Pope ◽  
Kijung Sung ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Mitochondrial Fission ◽  
Sensory Neuropathy ◽  
Selective Vulnerability ◽  
Mitochondrial Morphology ◽  
Physiological Level ◽  
Charcot Marie Tooth ◽  
Mitochondrial Movement ◽  
And Function ◽  
Peripheral Sensory

Recent evidence has uncovered an important role of Rab7 in regulating mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigated how mitochondrial morphology and function were impacted by the CMT2B associated Rab7V162M mutation in fibroblasts from human CMT2B patients as well as in a knockin mouse model. In contrast to recently published results from studies of using heterologous overexpression systems, our results have demonstrated significant mitochondrial fragmentation in fibroblasts of both human CMT2B patients and CMT2B mouse embryonic fibroblasts (MEFs). Furthermore, we have shown that mitochondria were fragmented and axonal mitochondrial movement was dysregulated in primary cultured E18 dorsal root ganglion (DRG) sensory neurons, but not in E18 hippocampal and cortical primary neurons. We also show that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalized the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study has revealed, for the first time, that expression of CMT2B Rab7 mutation at physiological level enhances Drp1 activity to promote mitochondrial fission, that may potentially underlie selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

scholarly journals Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects inCaenorhabditis elegans

2019 ◽  
Author(s):  
Ming S. Soh ◽  
Xinran Cheng ◽  
Jie Liu ◽  
Brent Neumann
Keyword(s):  
Sensory Neuropathy ◽  
Current Frequency ◽  
Charcot Marie Tooth ◽  
C Elegans ◽  
Muscle Structure ◽  
Electrophysiological Recordings ◽  
Morphological Defects ◽  
Underlying Mechanisms ◽  
And Function ◽  
Peripheral Motor

AbstractCharcot-Marie-Tooth (CMT) disease is an inherited peripheral motor and sensory neuropathy. The disease is divided into demyelinating (CMT1) and axonal (CMT2) neuropathies, and although we have gained molecular information into the details of CMT1 pathology, much less is known about CMT2. Due to its clinical and genetic heterogeneity, coupled with a lack of animal models, common underlying mechanisms remain elusive. In order to understand the biological importance of CMT2-casuative genes, we have studied the behavioural, cellular and molecular consequences of mutating nine different genes associated with CMT2 in the nematodeCaenorhabditis elegans(lin-41/TRIM2, dyn-1/DMN2, unc-116/KIF5A, fzo-1/MFN2, osm-9/TRPV4, cua-1/ATP7A, hsp-25/HSPB1, hint-1/HINT1, nep-2/MME). We show thatC. elegansdefective for these genes display debilitated movement in crawling and swimming assays. Severe morphological defects in cholinergic motors neurons are also evident in two of the mutants (dyn-1andunc-116). Furthermore, we establish novel methods for quantifying muscle morphology and use these to demonstrate striking loss of muscle structure across the mutants that correspond with reductions in muscle function. Finally, using electrophysiological recordings of neuromuscular junction (NMJ) activity, we uncover reductions in spontaneous postsynaptic current frequency inlin-41, dyn-1, unc-116andfzo-1mutants. By comparing the consequences of mutating numerous CMT2-related genes, this study reveals common deficits in muscle structure and function, as well as NMJ signalling when these genes are disrupted.

150 The Auditory and Vestibular Manifestations of Charcot Marie-Tooth Disease

1995 ◽  
Vol 113 (2) ◽  
pp. P203-P203
Author(s):  
Daniel R. Fear ◽  
C. Bruce MacDonald ◽  
L. Clarke Cox
Keyword(s):  
Hearing Loss ◽  
Muscle Atrophy ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Postural Changes ◽  
Brainstem Response ◽  
Peripheral Sensory ◽  
Tooth Disease

Objective: To present the auditory-vestibular manifestations of Charcot Marie-Tooth Disease (CMT). Case Report: A 53-year-old woman complained of progressive imbalance over 1 year. Imbalance was described as the sense that she was about to fall to one side, was exacerbated by rapid head acceleration, and had no relation to postural changes. Symptoms were continuous, and she fell multiple times. She used a cane for 1 year, but for the last month required a walker. Bilateral tinnitus and hearing loss developed over the last year. CMT had been diagnosed about 20 years earlier, with progressive distal limb weakness and wasting and peripheral sensory neuropathy. The neurotologic examination was normal except for the following: There was mild tremor in the left hand. Unsupported stance was unsteady, and she fell with eye closure. Vibrotactile sensation was reduced at the hands and ankles. Audiometry demonstrated a mild, somewhat asymmetric sensorineural hearing loss (SNHL). Auditory brainstem response showed poor waveform morphology bilaterally; however, the latencies for waves III and IV were within the normal range. Electronystagmography with rotary chair data showed hypofunction and reduced vestibulo-ocular gain. Ophthalmologic evaluation was refused. Discussion: CMT is an autosomal-dominant disorder manifested by progressive peripheral neuropathy, resulting in distal muscle atrophy and a peripheral sensory neuropathy. SNHL has been described in CMT. The Rosenberg-Chutorian Syndrome involves CMT with SNHL and optic atrophy. Other cranial neuropathies have also been described in CMT. Results: We describe a patient with CMT patient who had hearing loss and imbalance. The combination of vestibulopathy, sensory (proprioceptive) neuropathy, and muscle atrophy produced a devastating balance disorder. The literature on otologic manifestations of CMT is reviewed.

scholarly journals The Drosophila gene smoke alarm regulates nociceptor-epidermis interactions and thermal nociception behavior

2021 ◽  
Author(s):  
Stephanie Mauthner ◽  
Katherine Fisher ◽  
W. Daniel Tracey
Keyword(s):  
Sensory Neurons ◽  
Protein Function ◽  
Thermal Hyperalgesia ◽  
Loss Of Function ◽  
Smoke Alarm ◽  
Larval Body ◽  
Thermal Nociception ◽  
Bac Transgene ◽  
And Function ◽  
Peripheral Sensory

The detection and processing of noxious sensory input depends on the proper growth and function of nociceptor sensory neurons in the peripheral nervous system. In Drosophila melanogaster, the class IV (cIV) multidendritic dendritic arborization (md-da) neurons detect noxious stimuli through their highly branched dendrites that innervate the epidermis of the larval body wall. Here, we describe requirements of a previously uncharacterized gene named smoke alarm (smal), a discoidin domain receptor, in cIV md-da dendrite morphogenesis and nociception behavior. We find that smal mutant larvae exhibit thermal hyperalgesia that is fully rescued with a BAC transgene containing smal. Consistent with this phenotype, a smal reporter gene was expressed in nociceptors and other peripheral sensory neurons. Smal::GFP protein localized to punctate structures throughout the cIV md-da neurons. We further show that smal loss-of-function results in reduced nociceptor dendrite branching. Interestingly, mammalian homologues of smal act as collagen receptors, and we find that smal mutant dendrites showed an increase in epidermal cell ensheathment relative to animals that are wild type for smal. Based on this phenotype we propose that Smal protein function is required for attachment of dendrites to the extracellular matrix (ECM) and the loss of activity results in thermal hyperalgesia.

scholarly journals Dietary capsaicin normalizes CGRP peptidergic DRG neurons in experimental diabetic peripheral neuropathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiao-Yi Zhang ◽  
Zheng Guo ◽  
Tu-Ping Li ◽  
Tao Sun
Keyword(s):  
Sensory Neurons ◽  
Thermal Sensation ◽  
Gene Transfection ◽  
Sensory Nerve ◽  
Sensory Nerves ◽  
Drg Neurons ◽  
Specific Subset ◽  
Peripheral Sensory Neurons ◽  
And Function ◽  
Peripheral Sensory

AbstractDiabetic sensory neuropathy leads to impairment of peripheral sensory nerves and downregulation of calcitonin gene-related peptide (CGRP) in a functionally specific subset of peripheral sensory neurons mediating pain. Whether CGRP plays a neuroprotective role in peripheral sensory nerve is unclear. We evaluated alterations in noxious thermal sensation and downregulation of CGRP in the 8 weeks after induction of diabetes in rats. We supplemented capsaicin in the diet of the animals to upregulate CGRP and reversed the downregulation of the neuropeptide in the dorsal root ganglion (DRG) neurons dissociated from the diabetic animals, via gene transfection and exogenous CGRP, to test disease-preventing and disease-limiting effects of CGRP. Significant preservation of the nociceptive sensation, CGRP in spinal cord and DRG neurons, and number of CGRP-expressing neurons was found in the diabetic animals given capsaicin. Improvement in the survival of the neurons and the outgrowth of neurites was achieved in the neurons transfected by LV-CGRP or by exogenous CGRP, paralleling the correction of abnormalities of intracellular reactive oxygen species and mitochondrial transmembrane potentials. The results suggest that downregulation of CGRP impairs viability, regeneration and function of peripheral sensory neurons while capsaicin normalizes the CGRP peptidergic DRG neurons and function of the sensory nerves.

scholarly journals Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules

2013 ◽  
Vol 201 (7) ◽  
pp. 1037-1051 ◽  
Author(s):  
Stefan Strack ◽  
Theodore J. Wilson ◽  
J. Thomas Cribbs
Keyword(s):  
Alternative Splicing ◽  
Splice Variants ◽  
Mitochondrial Fission ◽  
Alternative Exon ◽  
Mitochondrial Morphology ◽  
Related Protein ◽  
Fusion Reactions ◽  
Mitochondrial Fragmentation ◽  
Cyclin Dependent Kinases ◽  
And Function

Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate–hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously unknown functional significance. Here, we report that splice variants including the third but excluding the second alternative exon (x01) localized to and copurified with microtubule bundles as dynamic polymers that resemble fission complexes on mitochondria. A major isoform in immune cells, Drp1-x01 required oligomeric assembly and Arg residues in alternative exon 3 for microtubule targeting. Drp1-x01 stabilized and bundled microtubules and attenuated staurosporine-induced mitochondrial fragmentation and apoptosis. Phosphorylation of a conserved Ser residue adjacent to the microtubule-binding exon released Drp1-x01 from microtubules and promoted mitochondrial fragmentation in a splice form–specific manner. Phosphorylation by Cdk1 contributed to dissociation of Drp1-x01 from mitotic microtubules, whereas Cdk5-mediated phosphorylation modulated Drp1-x01 targeting to interphase microtubules. Thus, alternative splicing generates a latent, cytoskeletal pool of Drp1 that is selectively mobilized by cyclin-dependent kinase signaling.

scholarly journals Dissection of the Carboxyl-Terminal Domain of the Proteasomal Subunit Rpn11 in Maintenance of Mitochondrial Structure and Function

2008 ◽  
Vol 19 (3) ◽  
pp. 1022-1031 ◽  
Author(s):  
Teresa Rinaldi ◽  
Line Hofmann ◽  
Alessia Gambadoro ◽  
Raynald Cossard ◽  
Nurit Livnat-Levanon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Amino Acids ◽  
Mitochondrial Fission ◽  
Mitochondrial Morphology ◽  
Terminal Part ◽  
C Terminus ◽  
Mitochondrial Defects ◽  
In Trans ◽  
Α Helix ◽  
And Function

We have previously demonstrated that the C-terminal part of Rpn11, a deubiquitinating enzyme in the lid of the proteasome, is essential for maintaining a correct cell cycle and normal mitochondrial morphology and function. The two roles are apparently unlinked as the mitochondrial role is mapped to the Carboxy-terminus, whereas the catalytic deubiquitinating activity is found within the N-terminal region. The mitochondrial defects are observed in rpn11-m1 (originally termed mpr1-1), a mutation that generates Rpn11 lacking the last 31 amino acids. No mitochondrial phenotypes are recorded for mutations in the MPN+/JAMM motif. In the present study, we investigated the participation of the last 31 amino acids of the Rpn11 protein by analysis of intragenic revertants and site-specific mutants. We identified a putative α-helix necessary for the maintenance of a correct cell cycle and determined that a very short region at the C-terminus of Rpn11 is essential for the maintenance of tubular mitochondrial morphology. Furthermore, we show that expression of the C-terminal part of Rpn11 is able to complement in trans all of the rpn11-m1 mitochondrial phenotypes. Finally, we investigate the mechanisms by which Rpn11 controls the mitochondrial shape and show that Rpn11 may regulate the mitochondrial fission and tubulation processes.

scholarly journals Increased mitochondrial fission of glomerular podocytes in diabetic nephropathy

2019 ◽  
Vol 8 (8) ◽  
pp. 1206-1212 ◽  
Author(s):  
Yiqiong Ma ◽  
Zhaowei Chen ◽  
Yu Tao ◽  
Jili Zhu ◽  
Hongxia Yang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Aspect Ratio ◽  
Protein Level ◽  
Mitochondrial Fission ◽  
Critical Factor ◽  
Pathological Process ◽  
Computer Assisted ◽  
Mitochondrial Morphology ◽  
Urine Protein ◽  
And Function

Aims Previous studies showed that abnormal mitochondrial structure and function were involved in the pathological process of diabetic nephropathy (DN). The dynamic mitochondrial processes, including fusion and fission, maintain the mass and quantity of mitochondria. Podocyte injury is a critical factor in the development and progression of DN. The present study evaluated the mitochondrial fission of podocytes in patients with DN. Methods We recruited 31 patients with biopsy-confirmed DN. A quantitative analysis of the mitochondrial morphology was conducted with electron microscopy using a computer-assisted morphometric analysis application to calculate the aspect ratio values. Immunofluorescence assays were used to evaluate protein colocalization in the glomeruli of patients. Results The urine protein level was significantly increased in DN patients compared to non-DN patients (P < 0.001), and the mitochondria in the podocytes from DN patients were more fragmentated than those from patients without DN. The mitochondrial aspect ratio values were negatively correlated with the proteinuria levels (r = −0.574, P = 0.01), and multiple regression analysis verified that the mitochondrial aspect ratio was significantly and independently associated with the urine protein level (β = −0.519, P = 0.007). In addition, Drp1, a mitochondrial fission factor, preferentially combines with AKAP1, which is located in the mitochondrial membrane. Conclusions In the podocytes of DN patients, mitochondrial fragmentation was increased, and mitochondrial aspect ratio values were correlated with the proteinuria levels. The AKAP1-Drp1 pathway may contribute to mitochondrial fission in the pathogenesis of DN.

Actin(g) on mitochondria – a role for cofilin1 in neuronal cell death pathways

2019 ◽  
Vol 400 (9) ◽  
pp. 1089-1097 ◽  
Author(s):  
Lena Hoffmann ◽  
Marco B. Rust ◽  
Carsten Culmsee
Keyword(s):  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Actin Dynamics ◽  
Organelle Transport ◽  
Mitochondrial Morphology ◽  
Cell Death Pathways ◽  
Key Factor ◽  
Mitochondrial Membrane Permeabilization ◽  
And Function

AbstractActin dynamics, the coordinated assembly and disassembly of actin filaments (F-actin), are essential for fundamental cellular processes, including cell shaping and motility, cell division or organelle transport. Recent studies highlighted a novel role for actin dynamics in the regulation of mitochondrial morphology and function, for example, through mitochondrial recruitment of dynamin-related protein 1 (Drp1), a key factor in the mitochondrial fission machinery. Mitochondria are dynamic organelles, and permanent fission and fusion is essential to maintain their function in energy metabolism, calcium homeostasis and regulation of reactive oxygen species (ROS). Here, we summarize recent insights into the emerging role of cofilin1, a key regulator of actin dynamics, for mitochondrial shape and function under physiological conditions and during cellular stress, respectively. This is of peculiar importance in neurons, which are particularly prone to changes in actin regulation and mitochondrial integrity and function. In neurons, cofilin1 may contribute to degenerative processes through formation of cofilin-actin rods, and through enhanced mitochondrial fission, mitochondrial membrane permeabilization, and the release of cytochrome c. Overall, mitochondrial impairment induced by dysfunction of actin-regulating proteins such as cofilin1 emerge as important mechanisms of neuronal death with relevance to acute brain injury and neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease.

scholarly journals Integrins protect sensory neurons in models of paclitaxel-induced peripheral sensory neuropathy

2021 ◽  
Vol 118 (15) ◽  
pp. e2006050118 ◽  
Author(s):  
Grace Ji-eun Shin ◽  
Maria Elena Pero ◽  
Luke A. Hammond ◽  
Anita Burgos ◽  
Atul Kumar ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Therapeutic Potential ◽  
Sensory Neuropathy ◽  
Nociceptive Neuron ◽  
Cellular Mechanisms ◽  
Recycling Endosomes ◽  
Nociceptive Neurons ◽  
Nociceptive Responses ◽  
Peripheral Sensory ◽  
Paclitaxel Treatment

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.

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