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

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 d...

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Bibliographic Details
Published in:PloS one 2014-10, Vol.9 (10), p.e111238
Main Authors: Scherf, Jacob M, Hu, Xiaoyang Serene, Tepp, William H, Ichtchenko, Konstantin, Johnson, Eric A, Pellett, Sabine
Format: Article
Language:English
Subjects:
Analysis
Axonogenesis
Bacteriology
Biology and Life Sciences
Botulinum toxin type A
Botulinum Toxins, Type A - pharmacology
Botulism
Calcium
Cells, Cultured
Cleavage
Cluster Analysis
Dehydrogenases
DNA microarrays
Drug dosages
Exposure
Food contamination
Gene expression
Gene Expression Profiling
Gene Expression Regulation - drug effects
Genes
Humans
Induced Pluripotent Stem Cells - cytology
Medicine and Health Sciences
Muscles
Neurons
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Paralysis
Pluripotency
Proteins
Reproducibility of Results
Research and Analysis Methods
Signal transduction
Stem cells
Studies
Time Factors
Waterborne diseases
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0111238