The Origin of Clostridial Neurotoxins

Tetanus is a syndrome that is often lethal, characterized by a spastic paralysis. Death follows bodily exhaustion and occurs by respiratory failure or circulatory collapse. For twenty four centuries tetanus had been considered a neurologic disease until the identification of C/os- diseases caused by tridium tetani, the bacterium that causes tetanus by the release of a clostridial neurotoxins protein toxin, named tetanus neurotoxin (TeTx)fFaber, 1890; Kitasato,

1891; Tizzoni and Cattani, 1890a,b).

Botulism, on the other hand, is characterized by a generalized muscular weakness. In its severe form, a generalized flaccid paralysis becomes evident in the victim and death results from respiratory failure (Hatheway, 1995). The causative agents of botulism are the neuro-toxigenic strains of Clostridium botulinum (van Ermengem, 1897), C. barati and C. butyricum (Hall et a/., 1985; Aureli et a/., 1986). So far, seven different serotypes of botulinum neurotoxin (BoNT), called A to G, have been identified. TeTx and BoNTs are the most potent toxins known. In fact, the 50 % lethal dose (LD50) in mice, human and horses varies between 0.1 ng and 1 ng of toxin per kg of body weight. Interestingly, different animal species show a great range of sensitivity to TeTx and to BoNTs. While mice are exquisitely sensitive to TeTx, rats and birds are quite resistant, and turtles are completely insensitive to TeTx effects (Payling-Wright, 1955).

The extreme toxicity of clostridial neurotoxins (CNTs) derives from their absolute neurospecificity as well as from catalytic activity. TeTx and BoNTs bind specifically to the neuromuscular junction (NMJ) of motor neurons. The identity of the receptor(s) on the presynaptic membrane is unknown, but their extreme toxicity suggests that the binding affinity to the cognate receptor must be very high. The receptor-bound toxin is internalized at the presynaptic membrane of the NMJ and gains access to the neuronal cytosol. Here it blocks the release of acetylcholine (ACh), causing a flaccid paralysis (Simpson, 1989). TeTx also binds to the presynaptic membrane of the motor neuron, but its action is limited to the level of the central nervous system. TeTx undergoes retrograde transport inside the motor neuron to the spinal cord (Bruschettini, 1892; Vallee and Bloom, 1991), where it migrates trans-synaptically into inhibitory interneurons (Simpson, 1989).

The blockade of inhibitory synapses at the spinal cord impairs the neuronal circuitry that controls voluntary muscle contraction, thereby causing the spastic paralysis characteristic of tetanus (Simpson, 1989).

The opposite clinical symptoms of tetanus and botulism result from the sites of action of TeTx and BoNTs within the nervous system, rather than from a different pathophysiological mechanism. TeTx acts on the central nervous system, while BoNTs exert their action on the peripheral nervous system. The only known activity of TeTx and BoNTs is a persistent inhibition of neurotransmitter release, including glycine, GABA, ACh, glutamate and norepinephrine. The release of opioids, oxytocin and vasopressin is also inhibited by CNTs (Wellhoner, 1992). The action of clostridial neurotoxins can be extended to different exo-cytotic events in a wide range of non-neuronal cells if the neurospe-cific binding and uptake processes are circumvented (Penner et a/., 1986; Bittner and Holz, 1988; Ahnert-Hilger et a/., 1989 a,b; Bittner et al., 1989 a,b; Stecher etal., 1989; Mclnnes and Dolly, 1990; Dayanithi et al., 1992, 1994; Ikonen et al., 1995; Regazzi et al., 1995; Sadoul et al., 1995).

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