Endocytosis, trafficking and exocytosis of intact full-length botulinum neurotoxin type a in cultured rat neurons

Valois, Luis Solabre; Wilkinson, Kevin A.; Nakamura, Yasuko; Henley, Jeremy M.

doi:10.1016/j.neuro.2020.02.009

Cited by 9 publications

(8 citation statements)

References 51 publications

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“…As a potent neurotoxin, BoNT inhibits neurotransmitter acetylcholine release from efferent nerves at neuromuscular junctions [ 9 ]. In the presynaptic space, BoNT enters the neuronal cell via receptor-mediated endocytosis [ 15 ]. BoNT subsequently separates into 50 KDa light chain and 100 KDa heavy chain in the endosomal vesicle [ 9 ].…”

Section: The Mechanism Of Bont-a In Functional Bladder Disordersmentioning

confidence: 99%

Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders

Jhang

Kuo

2021

Toxins

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Although intravesical botulinum toxin type A (BoNT-A) injection for functional bladder disorders is effective, the injection-related problems—such as bladder pain and urinary tract infection—make the procedure invasive and inconvenient. Several vehicles have recently been developed to deliver BoNT-A without injection, thereby making the treatment less or non-invasive. Laboratory evidence revealed that liposome can carry BoNT-A across the uroepithelium and act on sub-urothelial nerve endings. A randomized placebo controlled study revealed that intravesical administration of liposome-encapsulated BoNT-A and TC-3 hydrogel embedded BoNT-A can improve urinary frequency, urgency, and reduce incontinence in patients with overactive bladders. A single-arm prospective study also revealed that intravesical administration of TC-3 hydrogel embedded BoNT-A can relieve bladder pain in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We recently administered suprapubic energy shock wave (ESW) after BoNT-A intravesical administration in six patients with IC/BPS. Although pain reduction and symptom improvement were not significant, immunochemical staining showed cleaved synaptosome-associated protein 25 in the bladder after the procedure. This suggests that ESW can promote passage of BoNT-A across the uroepithelium. In conclusion, using vehicles to intra-vesically deliver BoNT-A for functional bladder disorders is promising. Further studies are necessary to confirm the efficacy and explore novel applications.

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Section: The Mechanism Of Bont-a In Functional Bladder Disordersmentioning

confidence: 99%

Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders

Jhang

Kuo

2021

Toxins

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“…Most studies suggest that BTX-A exerts its analgesic effects by releasing certain transmitters in the peripheral nervous system (such as calcitonin gene-related peptides, substance P and glutamate), anti-inflammatory and other modulation the peripheral nervous system (W.C. Lee et al, 2018;Muñoz-Lora et al, 2020;She et al, 2020). On the other hand, BTX-A exerts its therapeutic effect on pain by activating glial cells such as microglia and astrocytes and regulating the central nervous system-related pathways such as the upstream pain transmission pathway (Shi et al, 2019;Valois et al, 2020). However, to date, the specific targets of BTX-A action are not known, and the most likely targets are specific unknown receptors on the cell.…”

Section: Figure 1 Outline Of the Mechanism Of Btx-a In Treating Painmentioning

confidence: 99%

Advances in botulinum toxin type A for the treatment of pain

Jiang¹,

Huang²,

Yang³

et al. 2021

NRFHH

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<i>Clostridium botulinum</i> (CB) is a Gram-positive anaerobic bacterium and a significant cause of food spoilage. Foodborne botulism occurs worldwide every year and even lead to death from respiratory distress in severe cases after eating botulism-contaminated food. The pathogenicity of CB lies in its ability to produce a potent neurotoxin, “botulinum toxin (BTX)”, for which eight different subtypes have already been isolated so far. Botulinum toxin type A (BTX-A) is widely used to treat critical clinical issues due to its good affinity and tolerability. Studies have shown that BTX-A injections effectively treat myofascial pain, inflammatory pain, and neuropathic pain. The current article mainly reviews the latest research progress using BTX-A in pain treatment during two years.

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“…Interestingly, although BoNT/A predominantly enters neurons via synaptic vesicles at presynaptic terminals ( Colasante et al, 2013 ) it can also gain access via binding to the fibroblast growth factor receptor 3 (Fgfr3) which undergoes dynamin-independent endocytosis ( Jacky et al, 2013 , Solabre Valois et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Another option is to make the LC catalytically inactive and unable to cleave SNAP-25. The LC of BoNT/A is a zinc-dependent protease ( Schiavo et al, 1992 ) with the Zn 2+ ion fitting into a pocket formed by residues His223, Glu224, His227 and Glu262 ( Lacy et al, 1998 ) with Glu224 indirectly binding zinc through a water molecule (for entire sequence see ( Solabre Valois et al, 2020 )). Mutation of Glu224 to a structurally similar but oppositely charged residue (E224Q), or disrupting the zinc-binding pocket with a H227Y mutation completely remove LC catalytic activity ( Kukreja et al, 2007 , Zhou et al, 1995 ).…”

Section: Introductionmentioning

confidence: 99%

“…Here we investigated the effectiveness of the catalytically inactive full-length mutant of BoNT/A, BoNT/A(0), which contains two point mutations, E224Q/H227Y ( Solabre Valois et al, 2020 ) and HC C /A on neurite outgrowth. We performed experiments in neuronal stem cells and cultured rat hippocampal neurons in the presence or absence of the specific Rac1 inhibitor NSC23766 ( Gao et al, 2004 ) to investigate the effects and mechanisms of BoNT/A actions.…”

Section: Introductionmentioning

confidence: 99%

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Neurotrophic effects of Botulinum neurotoxin type A in hippocampal neurons involve activation of Rac1 by the non-catalytic heavy chain (HCC/A)

Valois

Shi

Bishop

et al. 2021

IBRO Neuroscience Reports

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Botulinum neurotoxins (BoNTs) are extremely potent naturally occurring poisons that act by silencing neurotransmission. Intriguingly, in addition to preventing presynaptic vesicle fusion, BoNT serotype A (BoNT/A) can also promote axonal regeneration in preclinical models. Here we report that the non-toxic C-terminal region of the receptor-binding domain of heavy chain BoNT/A (HC C /A) activates the small GTPase Rac1 and ERK pathway to potentiate axonal outgrowth, dendritic protrusion formation and synaptic vesicle release in hippocampal neurons. These data are consistent with HC C /A exerting neurotrophic properties, at least in part, independent of any BoNT catalytic activity or toxic effect.

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Endocytosis, trafficking and exocytosis of intact full-length botulinum neurotoxin type a in cultured rat neurons

Cited by 9 publications

References 51 publications

Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders

Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders

Advances in botulinum toxin type A for the treatment of pain

Neurotrophic effects of Botulinum neurotoxin type A in hippocampal neurons involve activation of Rac1 by the non-catalytic heavy chain (HCC/A)

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