title: Analysis of gene expression in induced pluripotent stem cell-derived human neurons exposed to botulinum neurotoxin A subtype 1 and a type A atoxic derivative.
abstract: Botulinum neurotoxin type A1 (BoNT/A1) is a potent protein toxin responsible for the potentially fatal human illness botulism. Notwithstanding, the long-lasting flaccid muscle paralysis caused by BoNT/A has led to its utility as a powerful and versatile bio-pharmaceutical. The flaccid paralysis is due to specific cleavage of neuronal SNAREs by BoNTs. However, actions of BoNTs on intoxicated neurons besides the cleavage of SNAREs have not been studied in detail. In this study we investigated by microarray analysis the effects of BoNT/A and a catalytically inactive derivative (BoNT/A ad) on the transcriptome of human induced pluripotent stem cell (hiPSC)-derived neurons at 2 days and 2 weeks after exposure. While there were only minor changes in expression levels at 2 days post exposure, at 2 weeks post exposure 492 genes were differentially expressed more than 2-fold in BoNT/A1-exposed cells when compared to non-exposed populations, and 682 genes were differentially expressed in BoNT/A ad-exposed cells. The vast majority of genes were similarly regulated in BoNT/A1 and BoNT/A ad-exposed neurons, and the few genes differentially regulated between BoNT/A1 and BoNT/A ad-exposed neurons were differentially expressed less than 3.5 fold. These data indicate a similar response of neurons to BoNT/A1 and BoNT/A ad exposure. The most highly regulated genes in cells exposed to either BoNT/A1 or BoNT/A ad are involved in neurite outgrowth and calcium channel sensitization.
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Scherf
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Xiaoyang Serene
authors.initials: XS
authors.lastname: Hu
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: William H
authors.initials: WH
authors.lastname: Tepp
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Ichtchenko
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Johnson
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pellett
mesh_terms: D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D002478:Cells, Cultured; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D019274:Botulinum Toxins, Type A