Anti-GQ1b antibodies and evoked acetylcholine release at mouse motor endplates

Bullens, Roland; O’Hanlon, Graham M.; Goodyear, Carl S.; Molenaar, Peter; Conner, Joe; Willison, Hugh J.; Plomp, Jaap J.

doi:10.1002/1097-4598(200007)23:7<1035::aid-mus5>3.0.co;2-r

Cited by 31 publications

(13 citation statements)

References 33 publications

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“…Therefore, any perturbation of the physiology of these gangliosides with antibodies may disturb the normal interactions between terminal axon and glia. This also identifies as presynaptic in origin (transmitter release changes) the structural scaffold responsible for the anti‐ganglioside antibody–induced alterations in neurotransmission previously described in acute experiments3 (see also articles by Buchwald and colleagues,1 Plomp and colleagues7, Bullens and colleagues25) and in a chronic model in this article. However, we showed3 that previous incubation with the P‐type VDCC channel blocker ω‐Aga‐IVA completely precludes the acute effect of IgM on quantal content and MEPP frequency, which strongly supports the involvement of the P‐type calcium channel that is localized in the presynaptic axonal membrane.…”

Section: Discussionsupporting

confidence: 52%

“…There have been electrophysiological studies into the acute effect of different patients' serum containing anti‐ganglioside antibodies (anti‐GM 1 , ‐GQ 1b , and ‐GM 2 ) from human autoimmune neuropathies (GBS, Miller–Fisher syndrome, and a pure motor chronic demyelinating polyneuropathy) on neurotransmitter release in the NMJ of rodents 1, 3, 7, 25. Both spontaneous and evoked transmitter release parameters were always altered.…”

Section: Discussionmentioning

confidence: 99%

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Changes in the neuromuscular synapse induced by an antibody against gangliosides

Santafé

Sabaté

García

et al. 2005

Annals of Neurology

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In this study, we used a monoclonal IgM antibody from a patient with a pure motor chronic demyelinating polyneuropathy, which binds specifically to the complex gangliosides GM(2), GalNAc-GD(1a), and GalNAc-GM(1b), which appear to have a common epitope of -[GalNAcbeta1-4Gal(3-2alphaNeuAc)beta1]. This was done for the following reasons: (1) to localize these gangliosides in specific cellular components of the neuromuscular junction (NMJ), and (2) to describe the anti-ganglioside antibody-induced structural and functional changes in the NMJs to gain insight into the role of gangliosides in the synaptic function. Using immunofluorescence techniques, we found that these gangliosides are located only in the presynaptic component of the motor end-plates, both in nerve terminals and in Schwann cells. After 2 weeks of continued passive transfer of the IgM monoclonal antibody over the mouse levator auris longus muscle, electromyography showed an axonal or NMJ disorder. Morphology showed important nerve terminal growth and retraction changes. Using intracellular recording electrophysiology, we found neurotransmitter release alterations, including quantal content reduction and an immature expression of voltage-dependent calcium channels similar to what occurred during NMJ development and regeneration. These changes were complement independent. The results showed that these gangliosides were involved in the reciprocal Schwann cell-nerve terminal interactions, including structural stability and neurotransmission.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Changes in the neuromuscular synapse induced by an antibody against gangliosides

Santafé

Sabaté

García

et al. 2005

Annals of Neurology

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“…In vitro electrophysiolog y. Microelectrode recordings were performed as described previously (Bullens et al, 2000). Briefly, microelectrode impalements were made at the endplate region of muscle fibers in preparations that had been treated with 3 M -Conotoxin GIII B (Scientific Marketing, Barnet, UK) to eliminate muscle action potentials by selective block of muscle Na ϩ channels (Cruz et al, 1985).…”

Section: Methodsmentioning

confidence: 99%

“…In view of the clinical resemblance between MFS and botulism, and the NMJ being the known botulinum neurotoxin target, the pathogenic effects of MFS sera and anti-GQ1b antibodies have been studied at mouse NMJs (Roberts et al, 1994;Buchwald et al, 1998;Goodyear et al, 1999;Plomp et al, 1999). One suggested pathophysiological mechanism is that anti-GQ1b antibodies bind to presynaptic GQ1b and induce a complementdependent, transient, and dramatic increase in spontaneous ACh release, followed by block of evoked release (Goodyear et al, 1999;Plomp et al, 1999;Bullens et al, 2000). This effect resembles that of ␣-Latrotoxin (␣LTx), and is accompanied by presynaptic destruction (O'Hanlon et al, 2001).…”

mentioning

confidence: 99%

Complex Gangliosides at the Neuromuscular Junction Are Membrane Receptors for Autoantibodies and Botulinum Neurotoxin But Redundant for Normal Synaptic Function

et al. 2002

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One specialization of vertebrate presynaptic neuronal membranes is their multifold enrichment in complex gangliosides, suggesting that these sialoglycolipids may play a major functional role in synaptic transmission. We tested this hypothesis directly by studying neuromuscular synapses of mice lacking complex gangliosides attributable to deletion of the gene coding for beta1,4 GalNAc-transferase (GM2/GD2 synthase), which catalyzes an early step in ganglioside synthesis. Our studies show that complex gangliosides are surprisingly redundant for regulated neurotransmitter release under normal physiological conditions. In contrast, we show that they are membrane receptors for both the paralytic botulinum neurotoxin type-A and human neuropathy-associated anti-ganglioside autoantibodies that arise through molecular mimicry with microbial structures. These data prove the critical importance of complex gangliosides in mediating pathophysiological events at the neuromuscular synapse.

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“…4 and ). Subsequently, we investigated whether block of evoked ACh release (measured as EPPs) either occurred directly, or secondarily after the dramatic increase in MEPP frequency (Bullens et al 2000). Before and after incubation of NMJs with purified anti‐GQ1b‐positive MFS IgG or the mouse anti‐GQ1b/GD3 mAb CGM3, we measured the evoked ACh release.…”

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confidence: 99%

Pathophysiological actions of neuropathy‐related anti‐ganglioside antibodies at the neuromuscular junction

Plomp

Willison

2009

The Journal of Physiology

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The outer leaflet of neuronal membranes is highly enriched in gangliosides. Therefore, specific neuronal roles have been attributed to this family of sialylated glycosphingolipids, e.g. in modulation of ion channels and transporters, neuronal interaction and recognition, temperature adaptation, Ca 2+ homeostasis, axonal growth, (para)node of Ranvier stability and synaptic transmission. Recent developmental, ageing and injury studies on transgenic mice lacking subsets of gangliosides indicate that gangliosides are involved in maintenance rather than development of the nervous system and that ganglioside family members are able to act in a mutually compensatory manner. Besides having physiological functions, gangliosides are the likely antigenic targets of autoantibodies present in Guillain-Barré syndrome (GBS), a group of neuropathies with clinical symptoms of motor-and/or sensory peripheral nerve dysfunction. Antibody binding to peripheral nerves is thought to either interfere with ganglioside function or activate complement, causing axonal damage and thereby disturbed action potential conduction. The presynaptic motor nerve terminal at the neuromuscular junction (NMJ) may be a prominent target because it is highly enriched in gangliosides and lies outside the blood-nerve barrier, allowing antibody access. The ensuing neuromuscular synaptopathy might contribute to the muscle weakness in GBS patients. Several groups, including our own, have studied the effects of anti-ganglioside antibodies in ex vivo and in vivo experimental settings at mouse NMJs. Here, after providing a background overview on ganglioside synthesis, localization and physiology, we will review those studies, which clearly show that anti-ganglioside antibodies are capable of binding to NMJs and thereby can exert a variety of pathophysiological effects. Furthermore, we will discuss the human clinical electrophysiological and histological evidence produced so far of the existence of a neuromuscular synaptopathy contributing to muscle weakness in GBS patients.

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Anti-GQ1b antibodies and evoked acetylcholine release at mouse motor endplates

Cited by 31 publications

References 33 publications

Changes in the neuromuscular synapse induced by an antibody against gangliosides

Changes in the neuromuscular synapse induced by an antibody against gangliosides

Complex Gangliosides at the Neuromuscular Junction Are Membrane Receptors for Autoantibodies and Botulinum Neurotoxin But Redundant for Normal Synaptic Function

Pathophysiological actions of neuropathy‐related anti‐ganglioside antibodies at the neuromuscular junction

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