Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model

Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model

The Mojave rattlesnake venom shows significant geographical variability. The venom of Type A animals primarily contains β-neurotoxin referred to as Mojave Toxin (MTX), which makes bites from this snake particularly feared. We performed a genome-wide transcriptomic analysis of the neurocellular respo...

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Main Authors: Satish Kumar, Miriam Aceves, Jose Granados, Lorena Guerra, Felicia Juarez, Earl Novilla, Ana C. Leandro, Marcelo Leandro, Juan Peralta, Sarah Williams-Blangero, Elda E. Sanchez, Jacob A. Galan, John Blangero, Joanne E. Curran
Format: Article
Language:English
Published: MDPI AG 2025-03-01
Series:Biomolecules
Subjects:
human iPSCs
NSCs
Mojave rattlesnake venom
neurocellular response
molecular mechanisms
Online Access:https://www.mdpi.com/2218-273X/15/3/381
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Summary:The Mojave rattlesnake venom shows significant geographical variability. The venom of Type A animals primarily contains β-neurotoxin referred to as Mojave Toxin (MTX), which makes bites from this snake particularly feared. We performed a genome-wide transcriptomic analysis of the neurocellular response to Mojave Type A rattlesnake venom using induced pluripotent stem cell-derived neural stem cells to unveil the molecular mechanisms underlying the damage caused by this snake’s envenomation. Our results suggest that snake venom metalloproteases, although having a limited repertoire in Type A venom, facilitate venom spread by digesting the tissue’s extracellular matrix. The MTX, which is composed of heterodimers of basic and acidic phospholipase-A2, co-opts the host arachidonic acid and Ca<sup>2+</sup> second messenger mechanisms and triggers multiple signaling cascades, such as the activation of MAPKs and NF-κB-regulated proinflammatory genes; the neurotransmitter overload in excitatory synapses leading to a presynaptic blockade of nerve signals; and the upregulation of unfolded protein response (UPR) due to the depletion of Ca<sup>2+</sup> from the endoplasmic reticulum. The upregulated UPR and the oxidative stress caused by reactive oxygen species generated in cytochromeP4501A1-mediated hydroxylation of arachidonic acid contribute to mitochondrial toxicity. The activation of UPR, mitochondrial toxicity, and oxidative stress synergistically contributed to apoptotic and ferroptotic cell death.
ISSN:2218-273X

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