scholarly journals Electrophysiological and Morphological Studies of SOD1 Transgenic Mice: An Animal Model of ALS

2021 ◽  
pp. 1-5
Author(s):  
David O. Carpenter ◽  
N Hori ◽  
Y Tan ◽  
Z Xu ◽  
N Akaike ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Motor Neurons ◽  
Lucifer Yellow ◽  
Cervical Spinal Cord ◽  
Membrane Resistance ◽  
Wild Type ◽  
Morphological Studies ◽  
Morphologic Characteristics ◽  
Excitatory Neurotransmitters ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a disease where upper and lower motor neurons die, and it is often associated with mutations of superoxide dismutase 1 (SOD1). We have used mouse models to compare physiologic and morphologic characteristics of cervical motor neurons in wild-type and mutant animals. Slices of the cervical spinal cord were prepared from old wild-type and mutant G93A and G85R mice, and intracellular recordings of membrane potential, resistance and responses to application of excitatory neurotransmitters were studied. Some motor neurons were injected with Lucifer Yellow for morphological analysis. There were no significant differences between membrane potential in the SOD1 mutants and aged wild-type mice, but membrane resistance was somewhat higher in the mutant motor neurons. Dendrites of the mutant motor neurons were not responsive to ionophoretic application of excitatory amino acids, although the cell body responded strongly. In Lucifer-filled cells, the dendrites were found to disappear. Mutant motor neurons were sometimes spontaneously active. Responses of mutant motor neurons to perfused glutamate with varying calcium concentrations in the Ringer’s solution were different from those of the wild-type cells.

Sustained membrane potential change of uropod motor neurons during the fictive abdominal posture movement in crayfish

1986 ◽  
Vol 56 (3) ◽  
pp. 702-717 ◽  
Author(s):  
M. Takahata ◽  
M. Hisada
Keyword(s):  
Membrane Potential ◽  
Motor Neurons ◽  
Membrane Resistance ◽  
Potential Change ◽  
Quiescent State ◽  
Membrane Potential Change ◽  
Synaptic Potentials ◽  
Nonspiking Interneurons ◽  
Body Rolling ◽  
Dendritic Branches

The occurrence of the uropod steering response as one of the equilibrium reflexes to body rolling in crayfish is significantly facilitated if the stimulus is given while the animal is performing the abdominal posture movement. This facilitation of the descending statocyst pathway by the abdominal posture system takes place between the uropod motor neurons and the statocyst interneurons, which directly project from the brain to the terminal abdominal ganglion where the motor neurons originate. To elucidate the synaptic mechanisms underlying the postural facilitation of the steering response, we analyzed in this study the activity of an identified set of uropod motor neurons during the fictive abdominal extension movement in the whole-animal preparation. Intracellular recordings from the dendritic branches of uropod motor neurons revealed that they were continuously excited during the fictive abdominal extension. The large fast motor neurons usually showed a sustained depolarization of the subthreshold magnitude. The small slow ones showed a suprathreshold sustained depolarization with spikes superimposed. Putative inhibitory motor neurons, on the other hand, showed a sustained hyperpolarization with their spontaneous spike discharge suppressed. The discrete synaptic potentials could hardly be distinguished and, instead, small fluctuations of the membrane potential were observed during the sustained depolarization of both the fast and slow motor neurons. Occasionally, large discrete synaptic potentials could be observed to be superimposed on the sustained depolarization. The occurring frequency of these synaptic potentials showed, however, no significant increase associated with the sustained depolarization. It hence seemed unlikely that these potentials were responsible for producing the sustained depolarization. Their amplitude during the sustained depolarization was smaller than that observed during the quiescent state. The sustained membrane potential change during the fictive abdominal movement was also observed in many neurons other than motor neurons, including local nonspiking interneurons and mechanosensory spiking interneurons. Both motor neurons and interneurons showed a decrease in their membrane resistance during the sustained membrane potential change. We concluded that the sustained depolarization of uropod motor neurons during the fictive abdominal extension was produced by the summation of small chemically transmitted postsynaptic potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiaki Furukawa
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Wild Type ◽  
Sporadic Als ◽  
Familial Form ◽  
Recent Developments ◽  
Lateral Sclerosis

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

scholarly journals GABA-like immunoreactivity in nonspiking interneurons of the locust metathoracic ganglion

2002 ◽  
Vol 205 (23) ◽  
pp. 3651-3659 ◽  
Author(s):  
M. Wildman ◽  
S. R. Ott ◽  
M. Burrows
Keyword(s):  
Membrane Potential ◽  
Motor Neurons ◽  
Lucifer Yellow ◽  
Current Injection ◽  
Aminobutyric Acid ◽  
Homogeneous Population ◽  
Metathoracic Ganglion ◽  
Nonspiking Interneurons ◽  
Intracellular Microelectrodes ◽  
Gaba Immunohistochemistry

SUMMARYNonspiking interneurons are important components of the premotor circuitry in the thoracic ganglia of insects. Their action on postsynaptic neurons appears to be predominantly inhibitory, but it is not known which transmitter(s) they use. Here, we demonstrate that many but not all nonspiking local interneurons in the locust metathoracic ganglion are immunopositive for GABA (γ-aminobutyric acid). Interneurons were impaled with intracellular microelectrodes and were shown physiologically to be nonspiking. They were further characterized by defining their effects on known leg motor neurons when their membrane potential was manipulated by current injection. Lucifer Yellow was then injected into these interneurons to reveal their cell bodies and the morphology of their branches. Some could be recognised as individuals by comparison with previous detailed descriptions. Ganglia were then processed for GABA immunohistochemistry. Fifteen of the 17 nonspiking interneurons studied were immunopositive for GABA, but two were not. The results suggest that the majority of these interneurons might exert their well-characterized effects on other neurons through the release of GABA but that some appear to use a transmitter other than GABA. These nonspiking interneurons are therefore not an homogeneous population with regard to their putative transmitter.

scholarly journals ALS-linked SOD1 Mutants Enhance Outgrowth, Branching, and the Formation of Actin-Based Structures in Adult Motor Neurons

2018 ◽  
Author(s):  
Zachary Osking ◽  
Jacob I. Ayers ◽  
Ryan Hildebrandt ◽  
Kristen Skruber ◽  
Hilda Brown ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Expression Profiling ◽  
Growth Cones ◽  
Therapeutic Strategies ◽  
Axonal Outgrowth ◽  
Wild Type ◽  
Mutant Sod1 ◽  
Dendritic Branching ◽  
Lateral Sclerosis ◽  
Cells Cultured

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by motor neuron cell death. However, not all motor neurons are equally susceptible. Most of what we know about the surviving motor neurons comes from gene expression profiling, less is known about their functional traits. We found that resistant motor neurons cultured from SOD1 ALS mouse models have enhanced axonal outgrowth and dendritic branching. They also have an increase in the number and size of actin-based structures like growth cones and filopodia. These phenotypes occur in cells cultured from presymptomatic mice and mutant SOD1 models that do not develop ALS, but not in embryonic motor neurons. Enhanced outgrowth and upregulation of filopodia can be induced in wild-type adult cells by expressing mutant SOD1. These results demonstrate that mutant SOD1 can enhance the regenerative capability of ALS resistant motor neurons. Capitalizing on this mechanism could lead to new therapeutic strategies.

scholarly journals Swim Training Ameliorates Hyperlocomotion of ALS Mice and Increases Glutathione Peroxidase Activity in the Spinal Cord

2021 ◽  
Vol 22 (21) ◽  
pp. 11614
Author(s):  
Katarzyna Patrycja Dzik ◽  
Damian Józef Flis ◽  
Zofia Kinga Bytowska ◽  
Mateusz Jakub Karnia ◽  
Wieslaw Ziolkowski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Glutathione Peroxidase ◽  
Motor Neurons ◽  
Wild Type ◽  
Mice Model ◽  
Behavioral Disturbances ◽  
Stress Markers ◽  
Last Stage ◽  
Lateral Sclerosis

(1) Background: Amyotrophic lateral sclerosis (ALS) is an incurable, neurodegenerative disease. In some cases, ALS causes behavioral disturbances and cognitive dysfunction. Swimming has revealed a neuroprotective influence on the motor neurons in ALS. (2) Methods: In the present study, a SOD1-G93A mice model of ALS were used, with wild-type B6SJL mice as controls. ALS mice were analyzed before ALS onset (10th week of life), at ALS 1 onset (first symptoms of the disease, ALS 1 onset, and ALS 1 onset SWIM), and at terminal ALS (last stage of the disease, ALS TER, and ALS TER SWIM), and compared with wild-type mice. Swim training was applied 5 times per week for 30 min. All mice underwent behavioral tests. The spinal cord was analyzed for the enzyme activities and oxidative stress markers. (3) Results: Pre-symptomatic ALS mice showed increased locomotor activity versus control mice; the swim training reduced these symptoms. The metabolic changes in the spinal cord were present at the pre-symptomatic stage of the disease with a shift towards glycolytic processes at the terminal stage of ALS. Swim training caused an adaptation, resulting in higher glutathione peroxidase (GPx) and protection against oxidative stress. (4) Conclusion: Therapeutic aquatic activity might slow down the progression of ALS.

scholarly journals Physiological and Pharmacological Studies on Cervical Motor Neurons in Slices Prepared from Neonatal and Aged Mice

2021 ◽  
pp. 1-5
Author(s):  
David O. Carpenter ◽  
N Hori ◽  
Z Xu ◽  
N Akaike ◽  
Y Tan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Motor Neurons ◽  
Excitatory Amino Acid ◽  
Lucifer Yellow ◽  
Membrane Resistance ◽  
Aged Mice ◽  
Lucifer Yellow Ch ◽  
Physiological Properties ◽  
Pharmacological Studies ◽  
Delayed Recovery

The effects of age on the physiological properties of cervical motor neurons were examined in slices made from an excised spinal cord graft of ICR mice from the second day after birth to age 350 days. The membrane potential of post-natal day 2 (PD2) to PD350 was about -65 mV and did not change greatly with age, although it was slightly higher at PD2. However, there were significant changes in membrane resistance, which increased with age from about 15 to 30 MΩ. The depolarization induced by the excitatory amino acid agonists, kainic acid, NMDA and AMPA, decreased with aging in spite of the increase in membrane resistance. The motor neurons of the aged mice showed delayed recovery from excitation caused by excitatory amino acid agonists. By injecting Lucifer yellow CH into motor neurons, it was observed that the dendrite trees become thin, and some of the dendrite branches were missing in older animals.

scholarly journals Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

2020 ◽  
Author(s):  
Edward Pokrishevsky ◽  
Michèle G. DuVal ◽  
Luke McAlary ◽  
Sarah Louadi ◽  
Silvia Pozzi ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Inclusion Bodies ◽  
Dna Binding Protein ◽  
Effector Proteins ◽  
Superoxide Dismutase 1 ◽  
Wild Type ◽  
Reporter Protein ◽  
Sporadic Als ◽  
Tryptophan Residues ◽  
Lateral Sclerosis

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated wild-type TAR DNA-binding protein 43 (TDP-43). Co-expression of mutant or wild-type TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein G85R-GFP in HEK293FT cells, and promotes synergistic axonopathy in zebrafish. This pathological interaction is dependent upon natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce wild-type SOD1 misfolding in HEK293FT cells, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in HEK293FT cells, and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.

scholarly journals Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes

2019 ◽  
Vol 90 (8) ◽  
pp. 861-869 ◽  
Author(s):  
Karin Forsberg ◽  
Karin Graffmo ◽  
Bente Pakkenberg ◽  
Markus Weber ◽  
Martin Nielsen ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Superoxide Dismutase 1 ◽  
Wild Type ◽  
Spinal Motor Neurons ◽  
Hexanucleotide Repeat ◽  
Cortical Motor ◽  
Spinal Motor ◽  
Repeat Expansions ◽  
Misfolded Sod1 ◽  
Lateral Sclerosis

ObjectiveA hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.MethodsA panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.ResultsThe 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1WT in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1WT inclusions. Minute amounts of misSOD1WT inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1D90A mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.Conclusions and relevanceAbundant inclusions containing misfolded SOD1WT are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1WT can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.

scholarly journals Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1077 ◽  
Author(s):  
Klatt ◽  
Theis ◽  
Hahn ◽  
Theiss ◽  
Matschke
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cervical Spinal Cord ◽  
Intrinsic Apoptotic Pathway ◽  
Apoptotic Pathway ◽  
Tissue Specific ◽  
Progressive Degeneration ◽  
Lateral Sclerosis ◽  
Apoptotic Cascade

Amyotrophic lateral sclerosis (ALS) is one of the most common incurable motor neuron disorders in adults. The majority of all ALS cases occur sporadically (sALS). Symptoms of ALS are caused by a progressive degeneration of motor neurons located in the motor cortex and spinal cord. The question arises why motor neurons selectively degenerate in ALS, while other cells and systems appear to be spared the disease. Members of the intrinsic apoptotic pathway are frequent targets of altered microRNA expression. Therefore, microRNAs and their effects on cell survival are subject of controversial debates. In this study, we investigated the expression of numerous members of the intrinsic apoptotic cascade by qPCR, western blot, and immunostaining in two different regions of the CNS of wobbler mice. Further we addressed the expression of miR-29b-3p targeting BMF, Bax, and, Bak, members of the apoptotic pathway. We show a tissue-specific differential expression of BMF, Bax, and cleaved-Caspase 3 in wobbler mice. An opposing regulation of miR-29b-3p expression in the cerebellum and cervical spinal cord of wobbler mice suggests different mechanisms regulating the intrinsic apoptotic pathway. Based on our findings, it could be speculated that miR-29b-3p might regulate antiapoptotic survival mechanisms in CNS areas that are not affected by neurodegeneration in the wobbler mouse ALS model.

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