Presynaptic neurotoxins: an expanding array of natural and modified molecules

The process of neurotransmitter release from nerve terminals is a target for a wide array of presynaptic toxins produced by various species, from humble bacteria to arthropods to vertebrate animals. Unlike other toxins, most presynaptic neurotoxins do not kill cells but simply inhibit or activate synaptic transmission. In this review, we describe two types of presynaptic neurotoxins: clostridial toxins and latrotoxins, which are, respectively, the most potent blockers and stimulators of neurotransmitter release. These toxins have been instrumental in defining presynaptic functions and are now widely used in research and medicine. Here, we would like to analyse the diversity of these toxins and demonstrate how the knowledge of their structures and mechanisms of action can help us to design better tools for research and medical applications. We will look at natural and synthetic variations of these exquisite molecular machines, highlighting recent advances in our understanding of presynaptic toxins and questions that remain to be answered. If we can decipher how a given biomolecule is modified by nature to target different species, we will be able to design new variants that carry only desired characteristics to achieve specific therapeutic, agricultural or research goals. Indeed, a number of research groups have already initiated a quest to harness the power of natural toxins with the aim of making them more specifically targeted and safer for future research and medical applications.