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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2025-03-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Satish Kumar |
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| description | 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. |
| format | Article |
| id | doaj-art-20bc1e57be8348f0b6bb31104a0b2d39 |
| institution | DOAJ |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-03-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-20bc1e57be8348f0b6bb31104a0b2d392025-08-20T02:42:39ZengMDPI AGBiomolecules2218-273X2025-03-0115338110.3390/biom15030381Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell ModelSatish Kumar0Miriam Aceves1Jose Granados2Lorena Guerra3Felicia Juarez4Earl Novilla5Ana C. Leandro6Marcelo Leandro7Juan Peralta8Sarah Williams-Blangero9Elda E. Sanchez10Jacob A. Galan11John Blangero12Joanne E. Curran13Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USANational Natural Toxin Research Center (NNTRC), Texas A&M University-Kingsville, Kingsville, TX 78363, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USADivision of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USAThe 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.https://www.mdpi.com/2218-273X/15/3/381human iPSCsNSCsMojave rattlesnake venomneurocellular responsemolecular mechanisms |
| spellingShingle | 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 Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model Biomolecules human iPSCs NSCs Mojave rattlesnake venom neurocellular response molecular mechanisms |
| title | Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model |
| title_full | Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model |
| title_fullStr | Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model |
| title_full_unstemmed | Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model |
| title_short | Neurocellular Stress Response to Mojave Type A Rattlesnake Venom: Study of Molecular Mechanisms Using Human iPSC-Derived Neural Stem Cell Model |
| title_sort | neurocellular stress response to mojave type a rattlesnake venom study of molecular mechanisms using human ipsc derived neural stem cell model |
| topic | human iPSCs NSCs Mojave rattlesnake venom neurocellular response molecular mechanisms |
| url | https://www.mdpi.com/2218-273X/15/3/381 |
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