IgG from amyotrophic lateral sclerosis affects tubular calcium channels of skeletal muscle

1991 ◽  
Vol 260 (6) ◽  
pp. C1347-C1351 ◽  
Author(s):  
O. Delbono ◽  
J. Garcia ◽  
S. H. Appel ◽  
E. Stefani
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Charge Movement ◽  
Mammalian Skeletal Muscle ◽  
Gap Technique ◽  
Voltage Dependent ◽  
Als Patients ◽  
Tubular Membranes ◽  
Ca2 Channels ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating human disease of upper and lower motoneurons. We studied the action of the immunoglobulin G (IgG) from ALS and disease control patients on dihydropyridine (DHP)-sensitive Ca2+ channels in single mammalian skeletal muscle fibers with the double Vaseline gap technique. The peak of the Ca2+ current (ICa) and the charge movement were reduced when the fibers were incubated in ALS IgG. These effects were lost when the IgG was boiled or adsorbed with skeletal tubular membranes. ALS IgG reduced skeletal muscle ICa in a similar fashion as nifedipine; the ICa blockade was voltage dependent, and the associated charge movement was reduced. These observations suggest that IgG from ALS patients reacts with the skeletal muscle DHP-sensitive Ca2+ channels or some associated regulatory moiety.

Fab fragments from amyotrophic lateral sclerosis IgG affect calcium channels of skeletal muscle

1993 ◽  
Vol 264 (3) ◽  
pp. C537-C543 ◽  
Author(s):  
O. Delbono ◽  
V. Magnelli ◽  
T. Sawada ◽  
R. G. Smith ◽  
S. H. Appel ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Specific Antigen ◽  
Charge Movement ◽  
Mammalian Skeletal Muscle ◽  
Fab Fragments ◽  
Als Patients ◽  
Ca2 Channels ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a human disease involving upper and lower motoneurons. In this paper we studied the action of specific antigen-binding site (Fab) fragments of immunoglobulins from ALS patients on dihydropyridine (DHP)-sensitive Ca2+ channel function in situ. Ca2+ channels in single mammalian skeletal muscle fibers tested by the double Vaseline gap technique and single Ca2+ channels reconstituted into bilayer were tested in these experiments. Although the observed current-voltage relationship was not modified by the addition of Fab fragments (1.5 mg/ml), peak Ca2+ current (ICa) was significantly reduced. The effect of these Fab fragments on the peak ICa reached a stable value after 60 min of incubation. ALS Fab fragments also slowed the ICa rising phase and increased the rate of tail current deactivation. Studies with double pulses demonstrated that ICa inactivation time course, voltage dependence, and recovery were not modified by ALS Fab fragments. Fab fragments from normal subjects and heat-inactivated Fab fragments from ALS patients did not induce any modification on the charge movement and ICa. In single channel studies, ALS Fab fragments reduced channels amplitude. These data support the concept of an immunological interaction between the circulating antibodies from ALS patients and DHP-sensitive Ca2+ channels.

scholarly journals IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival

2019 ◽  
Vol 116 (52) ◽  
pp. 26816-26822
Author(s):  
Yue Shi ◽  
Kyoung Sun Park ◽  
Seung Hyun Kim ◽  
Jia Yu ◽  
Kaixuan Zhao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cell Function ◽  
Islet Cells ◽  
Causal Link ◽  
Mouse Islet ◽  
Voltage Dependent ◽  
Islet Cell Function ◽  
Als Patients ◽  
Lateral Sclerosis

Patients with amyotrophic lateral sclerosis (ALS) often show hallmarks of type 2 diabetes mellitus (T2DM). However, the causal link between ALS and T2DM has remained a mystery. We now demonstrate that 60% of ALS patients with T2DM (ALS-T2DM) have sera that exaggerated K+-induced increases in cytosolic free Ca2+concentration ([Ca2+]i) in mouse islet cells. The effect was attributed to the presence of pathogenic immunoglobulin Gs (IgGs) in ALS-T2DM sera. The pathogenic IgGs immunocaptured the voltage-dependent Ca2+(CaV) channel subunit CaVα2δ1 in the plasma membrane enhancing CaV1 channel-mediated Ca2+influx and [Ca2+]i, resulting in impaired mitochondrial function. Consequently, impairments in [Ca2+]idynamics, insulin secretion, and cell viability occurred. These data reveal that patients with ALS-T2DM carry cytotoxic ALS-T2DM-IgG autoantibodies that serve as a causal link between ALS and T2DM by immunoattacking CaVα2δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.

scholarly journals Immunoglobulins from amyotrophic lateral sclerosis patients enhance the frequency of glycine-mediated spontaneous inhibitory postsynaptic currents in rat hypoglossal motoneurons

2007 ◽  
Vol 59 (4) ◽  
pp. 251-255 ◽  
Author(s):  
P.R. Andjus
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Hippocampal Neurons ◽  
Spontaneous Release ◽  
Hypoglossal Motoneurons ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Als Patients ◽  
Brain Stem Slices ◽  
Ca2 Channels ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating, still incurable neurological disorder affecting upper and lower motoneurons. Passive transfer of the disease occurs when immunoglobulins from ALS patients are injected into experimental animals. It is suggested that ALS IgGs cause excitotoxicity by acting on voltage-gated Ca2+ channels. We reported previously that ALS IgGs increase spontaneous release of glutamate in hippocampal neurons. Since these cells are not normally affected in ALS, we here studied the effect of ALS IgGs on hypoglossal motoneurons in rat brain-stem slices. The frequency of spontaneous glycine-mediated inhibitory postsynaptic currents (sIPSCs) was augmented, but not that of miniature ones (mIPSCs), thus pointing to an indirect effect on release.

scholarly journals Skeletal Muscle Remodelling as a Function of Disease Progression in Amyotrophic Lateral Sclerosis

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
L. Jensen ◽  
L. H. Jørgensen ◽  
R. D. Bech ◽  
U. Frandsen ◽  
H. D. Schrøder
Keyword(s):  
Cell Cycle ◽  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Morphological Changes ◽  
Immunohistochemical Markers ◽  
Before And After ◽  
Myogenic Factors ◽  
Als Patients ◽  
Lateral Sclerosis

Muscle weakness is considered the pivotal sign of amyotrophic lateral sclerosis (ALS). Knowledge about the skeletal muscle degeneration/regeneration process and the myogenic potential is limited in ALS patients. Therefore, we investigate these processes in a time course perspective by analysing skeletal muscle biopsies from ALS patients collected before and after a 12-week period of normal daily activities and compare these with healthy age-matched control tissue. We do this by evaluating mRNA and protein (immunohistochemical) markers of regeneration, neurodegeneration, myogenesis, cell cycle regulation, and inflammation. Our results show morphological changes indicative of active denervation and reinnervation and an increase in small atrophic fibres. We demonstrate differences between ALS and controls in pathways controlling skeletal muscle homeostasis, cytoskeletal and regenerative markers, neurodegenerative factors, myogenic factors, cell cycle determinants, and inflammatory markers. Our results on Pax7 and MyoD protein expression suggest that proliferation and differentiation of skeletal muscle stem cells are affected in ALS patients, and the myogenic processes cannot overcome the denervation-induced wasting.

scholarly journals The action of amyotrophic lateral sclerosis immunoglobulins on mammalian single skeletal muscle Ca2+ channels.

1993 ◽  
Vol 461 (1) ◽  
pp. 103-118 ◽  
Author(s):  
V Magnelli ◽  
T Sawada ◽  
O Delbono ◽  
R G Smith ◽  
S H Appel ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Ca2 Channels ◽  
Lateral Sclerosis

Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 17 (3) ◽  
pp. 275-285 ◽  
Author(s):  
Si Chen ◽  
Qiao Liao ◽  
Ke Lu ◽  
Jinxia Zhou ◽  
Cao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rat Model ◽  
Microglial Activation ◽  
Transgenic Rat ◽  
Intragastric Administration ◽  
Behavioral Deficits ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

Plasma Creatinine Level Does Not Predict Respiratory Function in Amyotrophic Lateral Sclerosis

2021 ◽  
pp. 1-5
Author(s):  
João Morgadinho ◽  
Ana Catarina Pronto-Laborinho ◽  
Vasco A. Conceição ◽  
Marta Gromicho ◽  
Susana Pinto ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Creatinine Level ◽  
Cox Regression ◽  
Functional Decline ◽  
Plasma Creatinine ◽  
Plasma Creatinine Level ◽  
Decline Rate ◽  
Respiratory Outcome ◽  
Als Patients ◽  
Lateral Sclerosis

In amyotrophic lateral sclerosis (ALS) lower plasma creatinine level has been associated with shorter survival and faster functional decline. It has not been clear if creatinine is associated with respiratory outcome. We analyzed retrospectively a population of unselected ALS patients. Multiple-regression and Cox-regression analyses were performed. We included 233 patients, mean age 62.8, mean disease duration of 18.6 months. At baseline, creatinine was significantly associated with ALSFRS-R, but not with its decline rate. No predictive value was disclosed for FVC, or their decline rate, or with survival. We did not confirm that creatinine is a marker of respiratory outcome.

Coping strategies among amyotrophic lateral sclerosis (ALS) patients: an integrative review

2021 ◽  
Author(s):  
Georgiana Soares Leandro ◽  
Mário Emílio Teixeira Dourado Júnior ◽  
Glauciane Costa Santana ◽  
Luan Samy Xavier Dantas
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Coping Strategies ◽  
Integrative Review ◽  
Als Patients ◽  
Lateral Sclerosis
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