Abstract
Botulinum neurotoxins are metalloproteases that specifically cleave N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in synaptic terminals, resulting in a potent inhibition of vesicle fusion and transmitter release. The family comprises different serotypes (BoNT/A to BoNT/G). The natural target of these toxins is represented by the neuromuscular junction, where BoNTs block acetylcholine release. In this review, we describe the actions of botulinum toxins after direct delivery to the central nervous system (CNS), where BoNTs block exocytosis of several transmitters, with near-complete silencing of neural networks. The use of clostridial neurotoxins in the CNS has allowed us to investigate specifically the role of synaptic activity in different physiological and pathological processes. The silencing properties of BoNTs can be exploited for therapeutic purposes, for example to counteract pathological hyperactivity and seizures in epileptogenic brain foci, or to investigate the role of activity in degenerative diseases like prion disease. Altogether, clostridial neurotoxins and their derivatives hold promise as powerful tools for both the basic understanding of brain function and the dissection and treatment of activity-dependent pathogenic pathways.
Highlights
Botulinum neurotoxins (BoNTs) are the pathogenic agents responsible for the manifestation of botulism
We describe the actions of botulinum toxins after direct delivery to the central nervous system (CNS), where BoNTs block exocytosis of several transmitters, with near-complete silencing of neural networks
Key Contribution: This review describes the experimental use of botulinum neurotoxins as tools to block synaptic function in specific brain modules and dissect activity-dependent pathways in Botulinum neurotoxins (BoNTs) are the pathogenic agents responsible for the manifestation of botulism
Summary
Botulinum neurotoxins (BoNTs) are the pathogenic agents responsible for the manifestation of botulism. The typical flaccid paralysis of botulism induced by BoNTs is due to blockade of cholinergic neurotransmission at the neuromuscular junction and autonomic terminals [1,2,3] These toxins are produce by anaerobic bacteria of the genus Clostridium and are among the most potent naturally-occurring substances. BoNTs share a common molecular structure and are composed of a disulphide-linked, ~100-kDa heavy chain and ~50-kDa light chain They are metalloproteases that bind to presynaptic terminals, enter the cytosol and block neurotransmitter release by specific cleavage of proteins of the soluble. Toxins 2018, 10, 175 synaptosomal associated protein of 25 kDa (SNAP-25); BoNT/C acts on both SNAP-25 and syntaxin; BoNT/B, D, F and G cleave vesicle-associated membrane proteins (VAMPs, known as synaptobrevins) Despite their toxicity, they produce a prolonged but reversible action at the synapses. We will describe how these potent and selective synaptic blockers may be exploited to gain insight into mechanisms of brain physiology and dysfunction
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