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

Luis Solabre Valois; H Shi; Paul N Bishop; Bangfu Zhu; Yasuko Nakamura; Kevin A Wilkinson; Jeremy M Henley

doi:10.1016/j.ibneur.2021.04.002

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

Luis Solabre Valois, H Shi, Paul N Bishop, Bangfu Zhu, Yasuko Nakamura, Kevin A Wilkinson^*, Jeremy M Henley^*

^*Corresponding author for this work

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Abstract

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 (HCC/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 HCC/A exerting neurotrophic properties, at least in part, independent of any BoNT catalytic activity or toxic effect

Original language	English
Pages (from-to)	196-207
Number of pages	12
Journal	IBRO Neuroscience Reports
Volume	10
DOIs	https://doi.org/10.1016/j.ibneur.2021.04.002
Publication status	Published - 13 May 2021

Bibliographical note

Funding Information:
We are grateful to Dina Anderson at Ipsen for championing this study and to Ipsen for funding LSV’s PhD. KAW and JMH thank the BBSRC ( BB/R00787X/1 ), the Leverhulme Trust ( RPG-2019-191 ) and a Wellcome Trust Investigatorship to JMH ( 220799/Z/20/Z ) for financial support to the lab. Sophie Duffel, an undergraduate project student, assisted in blotting for ERK activation in NSCs. We thank the Wolfson Bioimaging facility for assistance in the microscopy.

Funding Information:
We are grateful to Dina Anderson at Ipsen for championing this study and to Ipsen for funding LSV's PhD. KAW and JMH thank the BBSRC (BB/R00787X/1), the Leverhulme Trust (RPG-2019-191) and a Wellcome Trust Investigatorship to JMH (220799/Z/20/Z) for financial support to the lab. Sophie Duffel, an undergraduate project student, assisted in blotting for ERK activation in NSCs. We thank the Wolfson Bioimaging facility for assistance in the microscopy. LSV prepared all of the reagents, performed all of the experiments except the vesicle release assays and wrote the first draft of the manuscript; VS carried out the vesicle release assays; PB provided tools and advice; BZ provided expert training and advice in the preparation of neural stem cells; YN maintained excellent culture conditions and lab management; KAW provided guidance, advice and edited the manuscript; JMH provided guidance, managed the project and wrote the final manuscript. All the procedures used in this study were approved by the University of Bristol Animal Welfare and Ethics Review Body (ethics approval number UIN: UB/18/004) panel and the Biological and Genetic Modification Safety Committee (BGMSC).

Publisher Copyright:
© 2021 The Authors

Keywords

Botulinum neurotoxin
Neurotrophy
Rac1
ERK
Hippocampal neuron

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

abstract = "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 (HCC/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 HCC/A exerting neurotrophic properties, at least in part, independent of any BoNT catalytic activity or toxic effect",

keywords = "Botulinum neurotoxin, Neurotrophy, Rac1, ERK, Hippocampal neuron",

author = "{Solabre Valois}, Luis and H Shi and Bishop, {Paul N} and Bangfu Zhu and Yasuko Nakamura and Wilkinson, {Kevin A} and Henley, {Jeremy M}",

note = "Funding Information: We are grateful to Dina Anderson at Ipsen for championing this study and to Ipsen for funding LSV{\textquoteright}s PhD. KAW and JMH thank the BBSRC ( BB/R00787X/1 ), the Leverhulme Trust ( RPG-2019-191 ) and a Wellcome Trust Investigatorship to JMH ( 220799/Z/20/Z ) for financial support to the lab. Sophie Duffel, an undergraduate project student, assisted in blotting for ERK activation in NSCs. We thank the Wolfson Bioimaging facility for assistance in the microscopy. Funding Information: We are grateful to Dina Anderson at Ipsen for championing this study and to Ipsen for funding LSV's PhD. KAW and JMH thank the BBSRC (BB/R00787X/1), the Leverhulme Trust (RPG-2019-191) and a Wellcome Trust Investigatorship to JMH (220799/Z/20/Z) for financial support to the lab. Sophie Duffel, an undergraduate project student, assisted in blotting for ERK activation in NSCs. We thank the Wolfson Bioimaging facility for assistance in the microscopy. LSV prepared all of the reagents, performed all of the experiments except the vesicle release assays and wrote the first draft of the manuscript; VS carried out the vesicle release assays; PB provided tools and advice; BZ provided expert training and advice in the preparation of neural stem cells; YN maintained excellent culture conditions and lab management; KAW provided guidance, advice and edited the manuscript; JMH provided guidance, managed the project and wrote the final manuscript. All the procedures used in this study were approved by the University of Bristol Animal Welfare and Ethics Review Body (ethics approval number UIN: UB/18/004) panel and the Biological and Genetic Modification Safety Committee (BGMSC). Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = may,

day = "13",

doi = "10.1016/j.ibneur.2021.04.002",

language = "English",

volume = "10",

pages = "196--207",

journal = "IBRO Neuroscience Reports",

issn = "2667-2421",

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T1 - Neurotrophic effects of Botulinum neurotoxin type A in hippocampal neurons involve activation of Rac1 by the non-catalytic heavy chain (HCC/A)

AU - Solabre Valois, Luis

AU - Shi, H

AU - Bishop, Paul N

AU - Zhu, Bangfu

AU - Nakamura, Yasuko

AU - Wilkinson, Kevin A

AU - Henley, Jeremy M

N1 - Funding Information: We are grateful to Dina Anderson at Ipsen for championing this study and to Ipsen for funding LSV’s PhD. KAW and JMH thank the BBSRC ( BB/R00787X/1 ), the Leverhulme Trust ( RPG-2019-191 ) and a Wellcome Trust Investigatorship to JMH ( 220799/Z/20/Z ) for financial support to the lab. Sophie Duffel, an undergraduate project student, assisted in blotting for ERK activation in NSCs. We thank the Wolfson Bioimaging facility for assistance in the microscopy. Funding Information: We are grateful to Dina Anderson at Ipsen for championing this study and to Ipsen for funding LSV's PhD. KAW and JMH thank the BBSRC (BB/R00787X/1), the Leverhulme Trust (RPG-2019-191) and a Wellcome Trust Investigatorship to JMH (220799/Z/20/Z) for financial support to the lab. Sophie Duffel, an undergraduate project student, assisted in blotting for ERK activation in NSCs. We thank the Wolfson Bioimaging facility for assistance in the microscopy. LSV prepared all of the reagents, performed all of the experiments except the vesicle release assays and wrote the first draft of the manuscript; VS carried out the vesicle release assays; PB provided tools and advice; BZ provided expert training and advice in the preparation of neural stem cells; YN maintained excellent culture conditions and lab management; KAW provided guidance, advice and edited the manuscript; JMH provided guidance, managed the project and wrote the final manuscript. All the procedures used in this study were approved by the University of Bristol Animal Welfare and Ethics Review Body (ethics approval number UIN: UB/18/004) panel and the Biological and Genetic Modification Safety Committee (BGMSC). Publisher Copyright: © 2021 The Authors

PY - 2021/5/13

Y1 - 2021/5/13

N2 - 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 (HCC/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 HCC/A exerting neurotrophic properties, at least in part, independent of any BoNT catalytic activity or toxic effect

AB - 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 (HCC/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 HCC/A exerting neurotrophic properties, at least in part, independent of any BoNT catalytic activity or toxic effect

KW - Botulinum neurotoxin

KW - Neurotrophy

KW - Rac1

KW - ERK

KW - Hippocampal neuron

U2 - 10.1016/j.ibneur.2021.04.002

DO - 10.1016/j.ibneur.2021.04.002

M3 - Article (Academic Journal)

C2 - 34041508

VL - 10

SP - 196

EP - 207

JO - IBRO Neuroscience Reports

JF - IBRO Neuroscience Reports

SN - 2667-2421

ER -

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

Abstract

Bibliographical note

Keywords

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