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

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)
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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 languageEnglish
Pages (from-to)196-207
Number of pages12
JournalIBRO Neuroscience Reports
Volume10
DOIs
Publication statusPublished - 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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