Dapsone-Induced Distal Axonal Degeneration of the Motor Neurons

Dermatology ◽  
1978 ◽  
Vol 156 (6) ◽  
pp. 321-324 ◽  
Author(s):  
I. Helander ◽  
J. Partanen
Keyword(s):  
Motor Neurons ◽  
Axonal Degeneration ◽  
Distal Axonal Degeneration

scholarly journals MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons

2021 ◽  
Vol 14 ◽  
Author(s):  
Yongchao Mou ◽  
Joshua Dein ◽  
Zhenyu Chen ◽  
Mrunali Jagdale ◽  
Xue-Jun Li
Keyword(s):  
Protein Expression ◽  
Motor Neurons ◽  
Axonal Degeneration ◽  
Axonal Neuropathy ◽  
Motor Protein ◽  
Mitochondrial Morphology ◽  
Mitochondrial Transport ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Hesc Lines

Charcot-Marie-Tooth (CMT) disease is one of the most common genetically inherited neurological disorders and CMT type 2A (CMT 2A) is caused by dominant mutations in the mitofusin-2 (MFN2) gene. MFN2 is located in the outer mitochondrial membrane and is a mediator of mitochondrial fusion, with an essential role in maintaining normal neuronal functions. Although loss of MFN2 induces axonal neuropathy, the detailed mechanism by which MFN2 deficiency results in axonal degeneration of human spinal motor neurons remains largely unknown. In this study, we generated MFN2-knockdown human embryonic stem cell (hESC) lines using lentivirus expressing MFN2 short hairpin RNA (shRNA). Using these hESC lines, we found that MFN2 loss did not affect spinal motor neuron differentiation from hESCs but resulted in mitochondrial fragmentation and dysfunction as determined by live-cell imaging. Notably, MFN2-knockodwn spinal motor neurons exhibited CMT2A disease-related phenotypes, including extensive perikaryal inclusions of phosphorylated neurofilament heavy chain (pNfH), frequent axonal swellings, and increased pNfH levels in long-term cultures. Importantly, MFN2 deficit impaired anterograde and retrograde mitochondrial transport within axons, and reduced the mRNA and protein levels of kinesin and dynein, indicating the interfered motor protein expression induced by MFN2 deficiency. Our results reveal that MFN2 knockdown induced axonal degeneration of spinal motor neurons and defects in mitochondrial morphology and function. The impaired mitochondrial transport in MFN2-knockdown spinal motor neurons is mediated, at least partially, by the altered motor proteins, providing potential therapeutic targets for rescuing axonal degeneration of spinal motor neurons in CMT2A disease.

scholarly journals Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Aysel Cetinkaya-Fisgin ◽  
Xinghua Luan ◽  
Nicole Reed ◽  
Ye Eun Jeong ◽  
Byoung Chol Oh ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Side Effects ◽  
Cancer Cells ◽  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Adduct Formation ◽  
Calpain Activation ◽  
Chemotherapy Agent ◽  
Distal Axonal Degeneration ◽  
Calpain Inhibitors

AbstractCisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.

scholarly journals Chemically Induced Senescence in Human Stem Cell-Derived Neurons Promotes Phenotypic Presentation of Neurodegeneration

2021 ◽  
Author(s):  
Ali Fathi ◽  
Sakthikumar Mathivanan ◽  
Linghai Kong ◽  
Andrew J Petersen ◽  
Cole R.K Harder ◽  
...  
Keyword(s):  
Stem Cell ◽  
Small Molecules ◽  
Motor Neurons ◽  
Cortical Neurons ◽  
Axonal Degeneration ◽  
Human Stem Cell ◽  
Human Stem Cells ◽  
Embryonic Fibroblasts ◽  
Age Related ◽  
Chemically Induced

Modeling age-related neurodegenerative disorders with human stem cells is difficult due to the embryonic nature of stem cell derived neurons. We developed a chemical cocktail to induce senescence of iPSC-derived neurons to address this challenge. We first screened small molecules that induce embryonic fibroblasts to exhibit features characteristic of aged fibroblasts. We then optimized a cocktail of small molecules that induced senescence in fibroblasts and cortical neurons without causing DNA damage. The utility of the senescence cocktail was validated in motor neurons derived from ALS patient iPSCs which exhibited protein aggregation and axonal degeneration substantially earlier than those without cocktail treatment. Our senescence cocktail will likely enhance the manifestation of disease-related phenotypes in neurons derived from iPSCs, enabling the generation of reliable drug discovery platforms.

scholarly journals Distal Symmetrical Polyneuropathy in a Dog

1980 ◽  
Vol 17 (4) ◽  
pp. 422-435 ◽  
Author(s):  
K. G. Braund ◽  
P. J. Luttgen ◽  
R. W. Redding ◽  
P. F. Rumph
Keyword(s):  
Central Nervous System ◽  
Cell Proliferation ◽  
Axonal Degeneration ◽  
Neurologic Disease ◽  
Qualitative And Quantitative ◽  
Quantitative Studies ◽  
The Central Nervous System ◽  
Distal Symmetrical Polyneuropathy ◽  
Distal Axonal Degeneration ◽  
Dying Back

A 1.3-year-old Great Dane dog had a chronic progressive neurologic disease clinically expressed as a distal symmetrical polyneuropathy characterized by weakness and bilateral atrophy of bulbar and distal appendicular musculature. Qualitative and quantitative studies showed neurogenic atrophy of muscles below the elbow and stifle. There was Walleriantype degeneration. Schwann cell proliferation and cell bands of Büngner, and marked depletion of medium (5 to 8 μm) to large (9 to 15 μm) diameter myelinated fibers in the distal parts of appendicular and laryngeal nerves. Sensory (saphenous and superficial radial) and autonomic (sympathetic and dorsal vagal trunk) nerves were affected to a lesser degree. A distribution of distal axonal degeneration suggested a dying back process. The disease differed from classical dying back disorders by absence of axonal degeneration in selected pathways of the central nervous system.

scholarly journals Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy

2019 ◽  
Vol 116 (6) ◽  
pp. 2328-2337 ◽  
Author(s):  
Nathalie Bernard-Marissal ◽  
Gerben van Hameren ◽  
Manisha Juneja ◽  
Christophe Pellegrino ◽  
Lauri Louhivuori ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Axonal Degeneration ◽  
Calcium Handling ◽  
Gene Encoding ◽  
Mitofusin 2 ◽  
Charcot Marie Tooth ◽  
Tooth Type ◽  
Distal Axonal Degeneration

Mutations in theMFN2gene encoding Mitofusin 2 lead to the development of Charcot–Marie–Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2R94Qinduces distal axonal degeneration in the absence of overt neuronal death. The presence of mutant protein leads to reduction in endoplasmic reticulum and mitochondria contacts in CMT2A patient-derived fibroblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with endoplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly, pharmacological treatments reinforcing endoplasmic reticulum–mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2.

scholarly journals Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Éric Martineau ◽  
Adriana Di Polo ◽  
Christine Vande Velde ◽  
Richard Robitaille
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Axonal Degeneration ◽  
Synapse Formation ◽  
Neuromuscular Junctions ◽  
Motor Units ◽  
Early Event ◽  
Motor Neuron Degeneration ◽  
Single Motor Units

Despite being an early event in ALS, it remains unclear whether the denervation of neuromuscular junctions (NMJ) is simply the first manifestation of a globally degenerating motor neuron. Using in vivo imaging of single axons and their NMJs over a three-month period, we identify that single motor-units are dismantled asynchronously in SOD1G37R mice. We reveal that weeks prior to complete axonal degeneration, the dismantling of axonal branches is accompanied by contemporaneous new axonal sprouting resulting in synapse formation onto nearby NMJs. Denervation events tend to propagate from the first lost NMJ, consistent with a contribution of neuromuscular factors extrinsic to motor neurons, with distal branches being more susceptible. These results show that NMJ denervation in ALS is a complex and dynamic process of continuous denervation and new innervation rather than a manifestation of sudden global motor neuron degeneration.

Demyelinating Neuropathies

2017 ◽  
Author(s):  
John A. Goodfellow ◽  
Amy I. Davidson ◽  
Hugh J. Willison
Keyword(s):  
Molecular Structure ◽  
Axonal Degeneration ◽  
Pathophysiological Mechanism ◽  
Normal Process ◽  
Nodes Of Ranvier ◽  
Demyelinating Neuropathies ◽  
Distal Axonal Degeneration ◽  
Inherited Neuropathies

Many neuropathies have in common the basic pathophysiological mechanism of demyelination. Our understanding of the normal process of myelination and the molecular structure of myelin, nodes of Ranvier, and internodes has increased in recent years, yielding a greater understanding of the process of demyelination in disease. This chapter focuses on the inherited neuropathies as examples of non-inflammatory demyelinating neuropathies. For these conditions there are ongoing genotype-phenotype correlations and a greater appreciation of the importance of distal axonal degeneration as a consequence of demyelination.

scholarly journals Ethylene oxide induces central-peripheral distal axonal degeneration of the lumbar primary neurones in rats.

1985 ◽  
Vol 42 (6) ◽  
pp. 373-379 ◽  
Author(s):  
A Ohnishi ◽  
N Inoue ◽  
T Yamamoto ◽  
Y Murai ◽  
H Hori ◽  
...  
Keyword(s):  
Ethylene Oxide ◽  
Axonal Degeneration ◽  
Distal Axonal Degeneration
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