Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons.
Seven types (A-G) of botulinum neurotoxin (BoNT) target peripheral cholinergic neurons where they selectively proteolyze SNAP-25 (BoNT/A, BoNT/C1, and BoNT/E), syntaxin1 (BoNT/C1), and synaptobrevin (BoNT/B, BoNT/D, BoNT/F, and BoNT/G), SNARE proteins responsible for transmitter release, to cause neuromuscular paralysis but of different durations. BoNT/A paralysis lasts longest (4-6 months) in humans, hence its widespread clinical use for the treatment of dystonias. Molecular mechanisms underlying these distinct inhibitory patterns were deciphered in rat cerebellar neurons by quantifying the half-life of the effect of each toxin, the speed of replenishment of their substrates, and the degradation of the cleaved products, experiments not readily feasible at motor nerve endings. Correlation of target cleavage with blockade of transmitter release yielded half-lives of inhibition for BoNT/A, BoNT/C1, BoNT/B, BoNT/F, and BoNT/E (31, 25, approximately 10, approximately 2, and approximately 0.8 days, respectively), equivalent to the neuromuscular paralysis times found in mice, with recovery of release coinciding with reappearance of the intact SNAREs. A limiting factor for the short neuroparalytic durations of BoNT/F and BoNT/E is the replenishment of synaptobrevin or SNAP-25, whereas pulse labeling revealed that extended inhibition by BoNT/A, BoNT/B, or BoNT/C1 results from longevity of each protease. These novel findings could aid development of new toxin therapies for patients resistant to BoNT/A and effective treatments for human botulism.
Foran
Patrick G
PG
Centre for Neurobiochemistry, Department of Biological Sciences, Imperial College, London SW7 2AZ, United Kingdom.
Mohammed
Nadiem
N
Lisk
Godfrey O
GO
Nagwaney
Sharuna
S
Lawrence
Gary W
GW
Johnson
Eric
E
Smith
Leonard
L
Aoki
K Roger
KR
Dolly
J Oliver
JO
D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology*; D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000188:drug therapy*; D005089:Exocytosis / Q000187:drug effects*; D008565:Membrane Proteins / Q000032:analysis; D008715:Methionine / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D022622:Shiga Toxin 1 / Q000032:analysis; D050825:Synaptosomal-Associated Protein 25
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D022622:Shiga Toxin 1; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; C096323:rimabotulinumtoxinB; D008715:Methionine; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A; C096324:botulinum toxin type C; C096326:botulinum toxin type E; C096321:botulinum toxin type F