Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission
Introduction
BoNTs serotypes A-G, because of their unique potency and specificity for blocking transmission at the vertebrate neuromuscular junction (NMJ) are useful tools for studying transmitter release mechanisms, and long-term trophic interactions between nerve terminals, Schwann cells and muscle fibres. During the last decade, BoNTs have been sequenced, the target of their zinc-endopeptidase activity identified, and the crystal three-dimensional structure [41] and their complex with the substrates determined [33], [67], [75]. The discovery of their metalloprotease activity targeting key components of the exocytotic machinery has initiated a number of studies aimed at unravelling the intricate molecular mechanisms involved in the fusion of synaptic vesicles to the nerve terminal membrane. Since BoNTs give rise to a profound, albeit transient, paralysis when injected into skeletal muscle, a number of studies have been performed to investigate how the motoneuron and its synaptic cellular partners react to such a blockade of pre-synaptic regulated exocytosis and implement a cascade of events ultimately leading to the recovery of functional neuromuscular transmission. Motor nerve terminals are very stable throughout adulthood [64] but can undergo remarkable plasticity changes when challenged with BoNTs. The goal of this review is to summarise the molecular events involved in the blockade of neurotransmission and to examine the synaptic remodelling and recovery process taking place at BoNT-treated neuromuscular junctions.
Section snippets
Binding, internalisation and proteolytic activity of BoNTs at the nerve terminals
The neuronal acceptor(s) of BoNTs is/are still under investigation, but the characteristic of their selective binding to glycolipid and internalisation process have been described. They interact in vitro and in vivo with polysialogangliosides [31], [55], [56], in particular with members of the G1b series [7], [40], [47]. Gangliosides knockout mice [70] show a reduced sensitivity to the toxins [39] and fumonisin B1, an inhibitor of the synthesis of a wide range of glycolipids including
Blockade of quantal acetylcholine release
BoNTs drastically reduce both nerve-evoked and spontaneous quantal acetylcholine (ACh) release. The paralysis results from the inability of endplate potentials (EPPs) evoked by nerve stimuli to reach the appropriate membrane potential level to trigger an action potential in the muscle fibre [13], [30], [35], [50], [53], [60], [67], [72], [82]. Spontaneous quantal ACh release recorded as miniature endplate potentials (MEPPs) is also greatly reduced after exposure to BoNT/A [30], [50], [53], [60]
In vivo remodelling of the skeletal neuromuscular junction
A remarkable demonstration of synaptic plasticity is the ability of axons and nerve terminals of the skeletal neuromuscular system to sprout new processes and form synapses in response to the paralysis induced by BoNTs or to partial denervation. This requires changes in neuronal gene expression, de novo protein synthesis, and remodelling of synaptic contacts. Motoneurons have the ability to “sprout” new processes from their nerve terminals or nodes of Ranvier. Although many fundamental
Conclusions
The detailed analysis of BoNTs' mechanism of action has markedly improved our understanding of neurotransmitter release processes and the intricate molecular mechanisms involved in the fusion of synaptic vesicles to the nerve terminal membrane. In addition, several mechanisms are now being explored and will certainly yield new insights into synaptic vesicle trafficking within motoneurons.
Considerable evidence indicates that BoNTs promote synaptic remodelling at the NMJ. The sensor controlling
Acknowledgements
The authors' studies on botulinal neurotoxins were supported by research grants from The European Commission Biotechnology Program (grant BC104CT965119 to F.A.M.), Imperial Cancer Research Fund (to G.S.), the Association Française contre les Myopathies and the Direction des Systèmes de Forces et de la Prospective (grant DSP/STTC 01 34 029 to J. M.). The authors wish to thank the Franco-British Partnership Program Alliance (grant 00156SE) for facilitating the exchange between our laboratories.
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