Understanding the molecular mechanism underlying the presynaptic toxicity of secreted phospholipases A2
1Department of Molecular and Biomedical Sciences, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia.
Abstract:
An important group of toxins, whose action at the molecular level is still a matter of debate, is secreted phospholipases A(2) (sPLA(2)s) endowed with presynaptic or beta-neurotoxicity. The current belief is that these beta-neurotoxins (beta-ntxs) exert their toxicity primarily due to their extracellular enzymatic action on the plasma membrane of motoneurons at the neuromuscular junction. However, the discovery of several extra- and intracellular proteins, with high binding affinity for snake venom beta-ntxs, has raised the question as to whether this explanation is adequate to account for all the observed phenomena in the process of presynaptic toxicity. The purpose of this review is to critically examine the various published studies, including the most recent results on internalization of a beta-ntx into motor nerve terminals, in order to contribute to a better understanding of the molecular mechanism of beta-neurotoxicity. As a result, we propose that presynaptic neurotoxicity of sPLA(2)s is a result of both extra- and intracellular actions of beta-ntxs, involving enzymatic activity as well as interaction of the toxins with intracellular proteins affecting the cycling of synaptic vesicles in the axon terminals of vertebrate motoneurons.
Insights
Secreted phospholipases A(2) (sPLA(2)s) cause presynaptic neurotoxicity through both external enzymatic action and internal interactions with motor neuron proteins, affecting synaptic vesicle cycling.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Secreted phospholipases A(2) (sPLA(2)s) are toxins known for presynaptic neurotoxicity.
- Current understanding attributes their toxicity to extracellular enzymatic action on motoneuron plasma membranes.
- Recent discoveries of intracellular binding proteins challenge this solely extracellular mechanism.
Purpose of the Study:
- To critically review studies on beta-neurotoxin (beta-ntx) action.
- To investigate the internalization of beta-ntxs into motor nerve terminals.
- To elucidate the molecular mechanisms underlying presynaptic neurotoxicity.
Main Methods:
- Literature review of published studies on sPLA(2) neurotoxicity.
- Analysis of research on beta-ntx binding affinities for extra- and intracellular proteins.
- Examination of data regarding the internalization of beta-ntxs.
Main Results:
- sPLA(2)s exhibit presynaptic neurotoxicity.
- Evidence suggests beta-ntxs can be internalized into motor nerve terminals.
- Intracellular binding proteins interact with beta-ntxs.
Conclusions:
- Presynaptic neurotoxicity of sPLA(2)s involves both extracellular and intracellular mechanisms.
- Toxicity results from enzymatic activity and interactions with intracellular proteins.
- These interactions impact synaptic vesicle cycling in vertebrate motoneurons.
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