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

Authors

Satish Kumar, The University of Texas Rio Grande ValleyFollow
Miriam Aceves, The University of Texas Rio Grande ValleyFollow
Jose C. Granados, The University of Texas Rio Grande ValleyFollow
Lorena Guerra, The University of Texas Rio Grande Valley
Felicia Juarez, The University of Texas Rio Grande Valley
Earl Novilla, The University of Texas Rio Grande Valley
Ana C. Leandro, The University of Texas Rio Grande ValleyFollow
Marcelo Leandro, The University of Texas Rio Grande ValleyFollow
Juan M. Peralta, The University of Texas Rio Grande ValleyFollow
Sarah Williams-Blangero, The University of Texas Rio Grande ValleyFollow
Elda E. Sánchez, Texas A&M University-Kingsville
Jacob Galan, The University of Texas Rio Grande ValleyFollow
John Blangero, The University of Texas Rio Grande ValleyFollow
Joanne E. Curran, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

3-6-2025

Abstract

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 Ca2+ 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 Ca2+ 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.

Comments

© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Recommended Citation

Kumar, S., Aceves, M., Granados, J., Guerra, L., Juarez, F., Novilla, E., C. Leandro, A., Leandro, M., Peralta, J., Williams-Blangero, S., Sanchez, E. E., Galan, J. A., Blangero, J., & Curran, J. E. (2025). Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model. Biomolecules, 15(3), 381. https://doi.org/10.3390/biom15030381

Creative Commons License

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

Publication Title

Biomolecules

DOI

10.3390/biom15030381

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics