Amyotrophic lateral sclerosis: Serum factors enhance spontaneous and evoked transmitter release at the neuromuscular junction

O’Shaughnessy, Thomas J.; Yan, Haidun; Kim, Jimok; Middlekauff, Eric H.; Lee, Kwang W.; Phillips, Lawrence H.; Kim, Jun; Kim, Yong I.

doi:10.1002/(sici)1097-4598(199801)21:1<81::aid-mus11>3.0.co;2-3

Cited by 24 publications

(15 citation statements)

References 30 publications

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“…Interestingly, ALS-IgG did not affect QC, contrasting with QC evaluated at low-stimulation frequency (O'Shaughnessy et al, 1998). However, ALS-IgG enhanced asynchronous release at physiological stimulation frequencies.…”

Section: Potential Functional Relevance Of Als-igg-sp In Als Patientsmentioning

confidence: 62%

“…Additionally, ALS-IgG consistently increased transmitter release in different NMJ preparations, including diaphragm muscle (Uchitel et al, 1988;O'Shaughnessy et al, 1998;Mohamed et al, 2002;Muchnik et al, 2002) and levator auris muscle of the mouse (Uchitel et al, 1992;Fratantoni et al, 2000) and guinea pig diaphragm muscle (O. D. Uchitel, unpublished results) and even in hippocampal cellular culture (Andjus et al, 1997). It did not increase transmitter release, however, in PC12 cells (Offen et al, 1998) and mouse extraocular NMJ (Mosier et al, 2000).…”

mentioning

confidence: 84%

“…O'Shaughnessy et al (1998) observed an increment in QC mediated by ALS-IgG at low frequency of electrical stimulation. However, studying anconeus muscles from ALS patients, Maselli et al (1993) detected a reduction in QC with respect to control patients.…”

Section: Als-igg Did Not Affect Action Potential-evoked Synaptic Tranmentioning

confidence: 96%

“…In rodents treated with IgG from ALS patients (ALS-IgG), a [Ca 2ϩ ] i increment associated with degenerative structural alterations in motoneurons and synaptic plasticity at neuromuscular transmission was also observed (Engelhardt et al, 1995;Fratantoni et al, 2000;Pullen and Humphreys, 2000;Pullen et al, 2004). ALS-IgG from ϳ50% of ALS patients trigger synaptic potentiation in spontaneous neuromuscular transmission, together with [Ca 2ϩ ] i increment (ex vivo), and can induce long-term neuromuscular dysfunction in vivo (Uchitel et al, 1988(Uchitel et al, , 1992Engelhardt et al, 1995;O'Shaughnessy et al, 1998;Mohamed et al, 2002). These findings suggest that ALS-IgG may be involved in ALS pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Calcium Signaling Pathways Mediating Synaptic Potentiation Triggered by Amyotrophic Lateral Sclerosis IgG in Motor Nerve Terminals

2006

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Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects particularly motoneurons. Several pieces of evidence suggested the involvement of autoimmune mechanisms mediated by antibodies in ALS. However, the significance of those antibodies in the disease and the underlying mechanisms are unknown. Here we showed that IgG purified from a group of sporadic ALS patients, but not familial ALS patients, specifically interact with the presynaptic membrane of motoneurons through an antigen-antibody interaction and modulated synaptic transmission. Immunoreactivity against nerve terminals showed strong correlation with synaptic modulation ability. In addition, several controls have ruled out the possibility for this synaptic modulation to be mediated through proteases or nonspecific effects. Effective IgG potentiated both spontaneous and asynchronous transmitter release. Application of pharmacological inhibitors suggested that activation of this increased release required a nonconstitutive Ca 2ϩ influx through N-type (Ca v 2.2) channels and phospholipase C activity and that activation of IP 3 and ryanodine receptors were necessary to both activate and sustain the increased release. Consistent with the notion that ALS is heterogeneous disorder, our results reveal that, in ϳ50% of ALS patients, motor nerve terminals constitutes a target for autoimmune response.

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Section: Potential Functional Relevance Of Als-igg-sp In Als Patientsmentioning

confidence: 62%

mentioning

confidence: 84%

Section: Als-igg Did Not Affect Action Potential-evoked Synaptic Tranmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Calcium Signaling Pathways Mediating Synaptic Potentiation Triggered by Amyotrophic Lateral Sclerosis IgG in Motor Nerve Terminals

2006

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“…Acute treatment of muscles with ALS-Abs increased the frequency of spontaneous and asynchronous transmitter releases in mouse or rat neuromuscular preparations [18, 34, 35, 55, 56, 58]. Although the acute exposure of the neuromuscular preparations to ALS-Abs induced an increase in MEPPs frequency, it is feasible that a longer exposure may result in a reduction of MEPPs frequency as observed in ALS patients [52].…”

Section: Humoral Factors and Antibodies From Als Patients That Affmentioning

confidence: 99%

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

et al. 2000

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Amyotrophic lateral sclerosis: Serum factors enhance spontaneous and evoked transmitter release at the neuromuscular junction

Cited by 24 publications

References 30 publications

Calcium Signaling Pathways Mediating Synaptic Potentiation Triggered by Amyotrophic Lateral Sclerosis IgG in Motor Nerve Terminals

Calcium Signaling Pathways Mediating Synaptic Potentiation Triggered by Amyotrophic Lateral Sclerosis IgG in Motor Nerve Terminals

Autoimmunity in Amyotrophic Lateral Sclerosis: Past and Present

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

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