SRC family kinase inhibitors antagonize the toxicity of multiple serotypes of botulinum neurotoxin in human embryonic stem cell-derived motor neurons.

Date

2015-05-01

Author

Kiriş, Erkan
Nuss, JE
Wanner, LM
Peyser, BD
Du, HT
Gomba, GY
Kota, KP
Panchal, RG
Gussio, R
Kane, CD
Tessarollo, L
Bavari, S

Metadata

Show full item record

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Item Usage Stats

74
views

0
downloads

Botulinum neurotoxins (BoNTs), the causative agents of botulism, are potent inhibitors of neurotransmitter release from motor neurons. There are currently no drugs to treat BoNT intoxication after the onset of the disease symptoms. In this study, we explored how modulation of key host pathways affects the process of BoNT intoxication in human motor neurons, focusing on Src family kinase (SFK) signaling. Motor neurons derived from human embryonic stem (hES) cells were treated with a panel of SFK inhibitors and intoxicated with BoNT serotypes A, B, or E (which are responsible for > 95 % of human botulism cases). Subsequently, it was found that bosutinib, dasatinib, KX2-391, PP1, PP2, Src inhibitor-1, and SU6656 significantly antagonized all three of the serotypes. Furthermore, the data indicated that the treatment of hES-derived motor neurons with multiple SFK inhibitors increased the antagonistic effect synergistically. Mechanistically, the small molecules appear to inhibit BoNTs by targeting host pathways necessary for intoxication and not by directly inhibiting the toxins' proteolytic activity. Importantly, the identified inhibitors are all well-studied with some in clinical trials while others are FDA-approved drugs. Overall, this study emphasizes the importance of targeting host neuronal pathways, rather than the toxin's enzymatic components, to antagonize multiple BoNT serotypes in motor neurons.

Subject Keywords

Motor neurons, Human embryonic stem cells, Src inhibitors, Botulinum neurotoxins, Cell-based assay, Drug discovery

URI

https://hdl.handle.net/11511/49250

Journal

Neurotoxicity research

DOI

https://doi.org/10.1007/s12640-015-9526-z

Collections

Department of Biology, Article

Suggestions

OpenMETU
Core

Recent developments in cell-based assays and stem cell technologies for botulinum neurotoxin research and drug discovery. Kiriş, Erkan; Burnett, JC; Soloveva, V; Kane, CD; Bavari, S (2014-03-01) Botulinum neurotoxins (BoNTs) are exceptionally potent inhibitors of neurotransmission, causing muscle paralysis and respiratory failure associated with the disease botulism. Currently, no drugs are available to counter intracellular BoNT poisoning. To develop effective medical treatments, cell-based assays provide a valuable system to identify novel inhibitors in a time- and costefficient manner. Consequently, cell-based systems including immortalized cells, primary neurons, and stem-cell derived neurons h...
Embryonic stem cell-derived motoneurons provide a highly sensitive cell culture model for botulinum neurotoxin studies, with implications for high-throughput drug discovery. Kiriş, Erkan; Burnett, JC; Kota, KP; Koh, DC; Wanner, LM; Torres-Melendez, E; Gussio, R; Tessarollo, L; Bavari, S (Elsevier BV, 2011-05-01) Botulinum neurotoxins (BoNTs) inhibit cholinergic synaptic transmission by specifically cleaving proteins that are crucial for neurotransmitter exocytosis. Due to the lethality of these toxins, there are elevated concerns regarding their possible use as bioterrorism agents. Moreover, their widespread use for cosmetic purposes, and as medical treatments, has increased the potential risk of accidental overdosing and environmental exposure. Hence, there is an urgent need to develop novel modalities to counter ...
CpG RNA: identification of novel single-stranded RNA that stimulates human CD14+CD11c+ monocytes. Sugiyama, T; Gürsel, Mayda; Takeshita, F; Coban, C; Conover, J; Kaisho, T; Akira, S; Klinman, DM; Ishii, KJ (The American Association of Immunologists, 2005-02-15) Synthetic immunostimulatory nucleic acids such as CpG DNA are being harnessed therapeutically as vaccine adjuvants, anticancer or antiallergic agents. Efforts to identify nucleic acid-based agents capable of more specifically modulating the immune system are being developed. The current study identifies a novel class of single-stranded oligoribonucleotides (ORN) containing unmethylated CpG motifs and a poly(G) run at the 3 end (CpG ORN) that directly stimulate human CD14 CD11c monocytes but not dendritic ...
Oligomerization and cell surface expression of recombinant GABA(A) receptors tagged in the delta subunit Oflaz, Furkan Enes; Son, Çağdaş Devrim; Arslan, Ayla (IMR Press, 2019-12-01) The gamma-Aminobutyric acid type A receptors (GABA(A) Rs) are heteropentameric chloride channels responsible for primary inhibition in the mammalian brain. Studies have shown the expression of recombinant GABA(A) R subunits tagged with the green fluorescent protein (GFP), a 26.9 kDa protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. This allows the formation of recombinant proteins essential for the development of relevant in-vitro and in-vivo methodologi...
TrkA in vivo function is negatively regulated by ubiquitination. Kiriş, Erkan; Yanpallewar, S; Dorsey, SG; Becker, J; Bavari, S; Palko, ME; Coppola, V; Tessarollo, L (2014-03-12) TrkA is a tyrosine kinase receptor required for development and survival of the peripheral nervous system. In the adult, TrkA and its ligand NGF are peripheral pain mediators, particularly in inflammatory pain states. However, how TrkA regulates the function of nociceptive neurons and whether its activity levels may lead to sensory abnormalities is still unclear. Here we report the characterization of a 3 aa (KFG) domain that negatively regulates TrkA level and function in response to NGF. Deletion of this ...

Citation Formats

E. Kiriş et al., “SRC family kinase inhibitors antagonize the toxicity of multiple serotypes of botulinum neurotoxin in human embryonic stem cell-derived motor neurons.,” Neurotoxicity research, pp. 384–98, 2015, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/49250.