A 45-year-old agricultural worker presents to the emergency department with a 2-day history of progressively worsening jaw stiffness, difficulty swallowing, and painful, uncontrollable muscle spasms in his back. Vital signs show a heart rate of 112/min and blood pressure of 165/95 mm Hg. Physical examination is notable for severe trismus, risus sardonicus, and opisthotonos. He reports stepping on a rusty nail in a barn two weeks ago and has not received any vaccinations since early childhood. The pathogenic mechanism underlying this patient's condition is driven by a potent protein exotoxin. Arrange the following steps in the correct chronological sequence to describe the molecular pathogenesis of this exotoxin, from initial neuronal contact to its ultimate synaptic effect.
- 1Binding of the heavy chain carboxyl-terminal domain to specific polysialogangliosides on the presynaptic membrane of peripheral lower motor neurons.
- 2Internalization into endosomes and microtubule-dependent retrograde axonal transport toward the anterior horn of the spinal cord.
- 3Exocytosis into the synaptic cleft and subsequent transcytosis into presynaptic terminals of adjacent inhibitory interneurons.
- 4Acidification of the endosome driving translocation of the light chain into the cytosol, followed by zinc-endopeptidase cleavage of synaptobrevin (VAMP).
- 5Irreversible failure of synaptic vesicle fusion, preventing the exocytosis of glycine and gamma-aminobutyric acid (GABA) into the synapse.