Amyotrophic lateral sclerosis IgG-treated neuromuscular junctions develop sensitivity to L-type calcium channel blocker

Fratantoni, Silvina A.; Weisz, G; Pardal, Ana; Reisin, Ricardo; Uchitel, Osvaldo D.

doi:10.1002/(sici)1097-4598(200004)23:4<543::aid-mus13>3.0.co;2-s

Cited by 31 publications

(15 citation statements)

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“…Strikingly, these studies examined only the effect of the sera or ALS-Abs on the cell body of motoneurons but not at the motor nerve terminal. Indeed, several alterations in ALS patients have been reported at the synaptic level [50–54] which is consistent with the physiological and morphological alterations reported in the neuromuscular junction (NMJ) from in vivo and ex vivo mouse and rat preparations [18, 34, 35, 38, 55–58]. …”

Section: Humoral Factors and Antibodies From Als Patients That Affsupporting

confidence: 74%

“…Morphological, biochemical, pharmacological, and physiological studies performed either in animal models, cell culture, or with ex vivo preparations support the existence of autoimmune mechanisms in ALS [14–18, 34–38]. Typical hallmarks of autoimmunity such as circulating immune complexes, higher frequency of a particular histocompatibility type, or association with other autoimmune diseases have been reported [39–41].…”

Section: Pathogenesismentioning

confidence: 99%

“…Additional electrophysiological studies on mouse muscles treated with ALS-Abs have revealed synaptic changes in the molecular machinery involved in neurotransmission [38]. Neuromuscular transmission, in physiological conditions, is mediated by P/Q-type voltage-dependent calcium channels (VDCC) [61, 62].…”

Section: Humoral Factors and Antibodies From Als Patients That Affmentioning

confidence: 99%

“…The L-type VDCC is expressed in motor nerve terminals [63]; however, this channel only participates in synaptic transmission in stages of high synaptic remodeling, such as after treatment with botulinum toxin type A, regenerating NMJ after crash of motor nerve and rodent neonatal muscles where maturation of NMJ takes place [62, 64–66]. The functional coupling of L-type VDCC [38] not only shows that the ALS-Abs may induce functional alterations, but also provides evidence of specific molecular and physiological synaptic modifications associated with NMJ regeneration. This is consistent with denervation and reinnervation changes observed in the SOD1 (superoxide dismutase-1) animal model and ALS patients [54].…”

Section: Humoral Factors and Antibodies From Als Patients That Affmentioning

confidence: 99%

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Autoimmunity in Amyotrophic Lateral Sclerosis: Past and Present

Pagani

González

Uchitel

2011

Neurology Research International

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting particularly motor neurons for which no cure or effective treatment is available. Although the cause of ALS remains unknown, accumulative evidence suggests an autoimmune mechanism of pathogenesis. In this paper, we will summarize the current research related to autoimmunity in the sporadic form of ALS and discuss the potential underlying pathogenic mechanisms and perspectives. Presented data supports the view that humoral immune responses against motor nerve terminals can initiate a series of physiological changes leading to alteration of calcium homeostasis. In turn, loss of calcium homeostasis may induce neuronal death through apoptotic signaling pathways. Additional approaches identifying specific molecular features of this hypothesis are required, which will hopefully allow us to develop techniques of early diagnosis and effective therapies.

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Section: Humoral Factors and Antibodies From Als Patients That Affsupporting

confidence: 74%

Section: Pathogenesismentioning

confidence: 99%

Section: Humoral Factors and Antibodies From Als Patients That Affmentioning

confidence: 99%

Section: Humoral Factors and Antibodies From Als Patients That Affmentioning

confidence: 99%

See 2 more Smart Citations

Autoimmunity in Amyotrophic Lateral Sclerosis: Past and Present

Pagani

González

Uchitel

2011

Neurology Research International

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“…Thus, ALS patients have increased PKA expression (the intracellular target of A 2A receptor activation) in the spinal cord [43], which could indicate a positive feedback response for a PKA saturation mechanism, where different proteins trigger the cAMP – PKA pathway, limiting A 2A receptor effects. Also immunoglobulins from ALS patients sera increased spontaneous release [44] by rendering L-type VGCC sensitive to stimuli [45], the signaling target of A 2A receptor activation. This could lead to abnormal interactions, resulting in impaired regulatory A 2A receptor recruitment of L-type VGCCs.…”

Section: Discussionmentioning

confidence: 97%

Adenosine A2A Receptors Activation Facilitates Neuromuscular Transmission in the Pre-Symptomatic Phase of the SOD1(G93A) ALS Mice, but Not in the Symptomatic Phase

et al. 2014

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Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease leading to motor neuron dysfunction resulting in impairment of neuromuscular transmission. A2A adenosine receptors have already been considered as a potential therapeutical target for ALS but their neuromodulatory role at the neuromuscular junction in ALS remains to be clarified. In the present work, we evaluated the effects of A2A receptors on neuromuscular transmission of an animal model of ALS: SOD1(G93A) mice either in the pre-symptomatic (4–6 weeks old) or in the symptomatic (12–14 weeks old) stage. Electrophysiological experiments were performed obtaining intracellular recordings in Mg2+ paralyzed phrenic nerve-hemidiaphragm preparations. Endplate potentials (EPPs), quantal content (q. c.) of EPPs, miniature endplate potentials (MEPPs) and giant miniature endplate potential (GMEPPs) were recorded. In the pre-symptomatic phase of the disease (4–6 weeks old mice), the selective A2A receptor agonist, CGS 21680, significantly enhanced (p<0.05 Unpaired t-test) the mean amplitude and q.c. of EPPs, and the frequency of MEPPs and GMEPPs at SOD1(G93A) neuromuscular junctions, the effect being of higher magnitude (p<0.05, Unpaired t-test) than age-matched control littermates. On the contrary, in symptomatic mice (12–14 weeks old), CGS 21680 was devoid of effect on both the amplitude and q.c. of EPPs and the frequency of MEPPs and GMEPPs (p<0.05 Paired t-test). The results herein reported clearly document that at the neuromuscular junction of SOD1(G93A) mice there is an exacerbation of A2A receptor-mediated excitatory effects at the pre-symptomatic phase, whereas in the symptomatic phase A2A receptor activation is absent. The results thus suggest that A2A receptors function changes with ALS progression.

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