IgM M-protein with antibody activity against gangliosides with disialosyl residue in sensory neuropathy binds to sensory neurons

We studied IgA immunoglobulins in nasal secretions in order to clarify mucosal immunity of the nasal cavity and paranasal sinuses during chronic nasal infection. Secretory IgA and serum type IgA of 165 samples of nasal secretions were analyzed quantitatively by use of electroimmunodiffusion techniques, and the specific antibody activity of secretory IgA against the M protein of Streptococcus pyogenes was investigated by use of enzyme-linked immunosorbent assay. Results show that although the secretory IgA content in nasal secretions was elevated in chronic sinusitis, its specific antibody activity against the M protein was lower than that in normal subjects. This evidence suggests that nonspecific secretory IgA antibodies are predominantly produced in chronic sinusitis, and that mucosal immunity preventing the adherence of bacteria is impaired in the diseased mucosa.

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Preferential loss of large lumbar primary sensory neurons in carcinomatous sensory neuropathy

Annals of Neurology ◽

10.1002/ana.410200119 ◽

1986 ◽

Vol 20 (1) ◽

pp. 102-104 ◽

Cited By ~ 23

Author(s):

Akio Ohnishi ◽

Michiko Ogawa

Keyword(s):

Sensory Neurons ◽

Sensory Neuropathy ◽

Primary Sensory Neurons ◽

Preferential Loss

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Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

10.1101/2021.07.28.454213 ◽

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.

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Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity

Advances in Nutrition ◽

10.1093/advances/nmab033 ◽

2021 ◽

Author(s):

Felix Hadtstein ◽

Misha Vrolijk

Keyword(s):

Peripheral Neuropathy ◽

Sensory Neurons ◽

Sensory Neuropathy ◽

Vitamin B ◽

Hereditary Neuropathy ◽

Pyridoxal Kinase ◽

Peripheral Tissues ◽

Adverse Health Effects ◽

Gaba Signaling ◽

Gaba Neurotransmission

ABSTRACT Vitamin B-6 in the form of pyridoxine (PN) is commonly used by the general population. The use of PN-containing supplements has gained lots of attention over the past years as they have been related to the development of peripheral neuropathy. In light of this, the number of reported cases of adverse health effects due to the use of vitamin B-6 have increased. Despite a long history of study, the pathogenic mechanisms associated with PN toxicity remain elusive. Therefore, the present review is focused on investigating the mechanistic link between PN supplementation and sensory peripheral neuropathy. Excessive PN intake induces neuropathy through the preferential injury of sensory neurons. Recent reports on hereditary neuropathy due to pyridoxal kinase (PDXK) mutations may provide some insight into the mechanism, as genetic deficiencies in PDXK lead to the development of axonal sensory neuropathy. High circulating concentrations of PN may lead to a similar condition via the inhibition of PDXK. The mechanism behind PDXK-induced neuropathy is unknown; however, there is reason to believe that it may be related to γ-aminobutyric acid (GABA) neurotransmission. Compounds that inhibit PDXK lead to convulsions and reductions in GABA biosynthesis. The absence of central nervous system-related symptoms in PDXK deficiency could be due to differences in the regulation of PDXK, where PDXK activity is preserved in the brain but not in peripheral tissues. As PN is relatively impermeable to the blood–brain barrier, PDXK inhibition would similarly be confined to the peripheries and, as a result, GABA signaling may be perturbed within peripheral tissues, such as sensory neurons. Perturbed GABA signaling within sensory neurons may lead to excitotoxicity, neurodegeneration, and ultimately, the development of peripheral neuropathy. For several reasons, we conclude that PDXK inhibition and consequently disrupted GABA neurotransmission is the most plausible mechanism of toxicity.

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Dystonin loss-of-function leads to impaired autophagy-endolysosomal pathway dynamics

Biochemistry and Cell Biology ◽

10.1139/bcb-2020-0557 ◽

2020 ◽

Author(s):

Anisha Lynch-Godrei ◽

Yves De Repentigny ◽

Andrew Ferrier ◽

Sabrina Gagnon ◽

Rashmi Kothary

Keyword(s):

Sensory Neurons ◽

Molecular Motors ◽

Motor Protein ◽

Sensory Neuropathy ◽

Autophagic Flux ◽

Loss Of Function ◽

Protein Levels ◽

Large Size ◽

Autonomic Disturbances

The neuronal dystonin protein (DST-a) is a large cytoskeletal linker important for integrating the various components of the cytoskeleton. Recessive Dst mutations lead to a sensory neuropathy in mice known as dystonia musculorum (Dstdt). The disease is characterized by ataxia, autonomic disturbances, and ultimately death, which are associated with massive dorsal root ganglion (DRG) sensory neuron degeneration. Recent investigation of Dstdt sensory neurons revealed an accumulation in autophagosomes and a disruption in autophagic flux, which was believed to be due to insufficient motor protein availability. Motor protein levels and the endolysosomal pathway were assessed in pre-symptomatic (postnatal day 5; P5) and symptomatic (P15) stage wild type and Dstdt DRGs. Levels of mRNA encoding molecular motors are reduced, although no significant reduction protein level is detected. An increase in lysosomal marker LAMP1 in medium-large size Dstdt-27J sensory neurons is observed, along with an accumulation of electron-light single-membraned vesicles in Dstdt-27J DRG tissue at late stages of disease. These vesicles are likely to be autolysosomes, and their presence in only late stage Dstdt-27J sensory neurons is suggestive of a pathological defect in autophagy. Further investigation is necessary to confirm vesicle identity, and to determine the role of Dst-a in normal autophagic flux.

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Neuropathy and Monoclonal IgM M-Protein with Antibody Activity Against Gangliosides

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1988.tb27106.x ◽

1988 ◽

Vol 540 (1 Advances in N) ◽

pp. 378-380 ◽

Cited By ~ 2

Author(s):

E. NARDELLI ◽

A. J. STECK ◽

M. SCHLUEP ◽

K. FELGENHAUER ◽

F. JERUSALEM

Keyword(s):

M Protein ◽

Antibody Activity

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2006050118 ◽

2021 ◽

Vol 118 (15) ◽

pp. e2006050118 ◽

Cited By ~ 1

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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