Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root ganglia
Our understanding of how sex and age influence chronic pain at the molecular level is still limited with wide-reaching consequences for adolescent patients. Here, we leveraged deep proteome profiling of mouse dorsal root ganglia (DRG) from adolescent (4-week-old) and adult (12-week-old) male and fem...
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Elsevier
2025-01-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824004973 |
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| author | Sabrina Grundtner Julia R. Sondermann Feng Xian Daniel Malzl Daniel Segelcke Esther M. Pogatzki-Zahn Jörg Menche David Gómez-Varela Manuela Schmidt |
| author_facet | Sabrina Grundtner Julia R. Sondermann Feng Xian Daniel Malzl Daniel Segelcke Esther M. Pogatzki-Zahn Jörg Menche David Gómez-Varela Manuela Schmidt |
| author_sort | Sabrina Grundtner |
| collection | DOAJ |
| description | Our understanding of how sex and age influence chronic pain at the molecular level is still limited with wide-reaching consequences for adolescent patients. Here, we leveraged deep proteome profiling of mouse dorsal root ganglia (DRG) from adolescent (4-week-old) and adult (12-week-old) male and female mice to investigate the establishment of neuropathic pain in the spared nerve injury (SNI)-model in parallel. We quantified over 12,000 proteins, including notable ion channels involved in pain, highlighting the sensitivity of our approach. Differential expression revealed sex- and age-dependent proteome changes upon nerve injury. In contrast to most previous studies, our comprehensive dataset enabled us to determine differentially expressed proteins (DEPs), which were shared between male and female mice of both age groups. Among these, the vast majority (94 %) were also expressed and, in part, altered in human DRG of neuropathic pain patients, indicating evolutionary conservation. Proteome signatures represented numerous targets of FDA-approved drugs comprising both (i) known pain therapeutics (e.g. Pregabalin and opioids) and, importantly, (ii) compounds with high potential for future re-purposing, e.g. Ptprc-modulators and Epoetins. Protein network and multidimensional analysis uncovered distinct hubs of sex- and age-shared biological pathways impacted by neuropathic pain, such as neuronal activity and synaptic function, DNA-damage, and neuroimmune interactions. Taken together, our results capture the complexity of nerve injury-associated DRG alterations in mice at the network level, moving beyond single-candidate studies. Consequently, we provide an innovative resource of the molecular landscape of neuropathic pain, enabling novel opportunities for translational pain research and network-based drug discovery. |
| format | Article |
| id | doaj-art-ecfccfad438947b79ad23957ab28ba98 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-ecfccfad438947b79ad23957ab28ba982025-01-09T06:13:04ZengElsevierPharmacological Research1096-11862025-01-01211107552Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root gangliaSabrina Grundtner0Julia R. Sondermann1Feng Xian2Daniel Malzl3Daniel Segelcke4Esther M. Pogatzki-Zahn5Jörg Menche6David Gómez-Varela7Manuela Schmidt8Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, AustriaDivision of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, AustriaDivision of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria; Department of Structural and Computational Biology, Center for Molecular Biology, University of Vienna, Vienna, AustriaClinic for Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, GermanyClinic for Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, GermanyCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria; Department of Structural and Computational Biology, Center for Molecular Biology, University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Network Medicine at the University of Vienna, Vienna, Austria; Faculty of Mathematics, University of Vienna, Vienna, AustriaDivision of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, AustriaDivision of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria; Corresponding author.Our understanding of how sex and age influence chronic pain at the molecular level is still limited with wide-reaching consequences for adolescent patients. Here, we leveraged deep proteome profiling of mouse dorsal root ganglia (DRG) from adolescent (4-week-old) and adult (12-week-old) male and female mice to investigate the establishment of neuropathic pain in the spared nerve injury (SNI)-model in parallel. We quantified over 12,000 proteins, including notable ion channels involved in pain, highlighting the sensitivity of our approach. Differential expression revealed sex- and age-dependent proteome changes upon nerve injury. In contrast to most previous studies, our comprehensive dataset enabled us to determine differentially expressed proteins (DEPs), which were shared between male and female mice of both age groups. Among these, the vast majority (94 %) were also expressed and, in part, altered in human DRG of neuropathic pain patients, indicating evolutionary conservation. Proteome signatures represented numerous targets of FDA-approved drugs comprising both (i) known pain therapeutics (e.g. Pregabalin and opioids) and, importantly, (ii) compounds with high potential for future re-purposing, e.g. Ptprc-modulators and Epoetins. Protein network and multidimensional analysis uncovered distinct hubs of sex- and age-shared biological pathways impacted by neuropathic pain, such as neuronal activity and synaptic function, DNA-damage, and neuroimmune interactions. Taken together, our results capture the complexity of nerve injury-associated DRG alterations in mice at the network level, moving beyond single-candidate studies. Consequently, we provide an innovative resource of the molecular landscape of neuropathic pain, enabling novel opportunities for translational pain research and network-based drug discovery.http://www.sciencedirect.com/science/article/pii/S1043661824004973Neuropathic painDorsal root gangliaPediatricProteomicsMEFISTOSystems pharmacology |
| spellingShingle | Sabrina Grundtner Julia R. Sondermann Feng Xian Daniel Malzl Daniel Segelcke Esther M. Pogatzki-Zahn Jörg Menche David Gómez-Varela Manuela Schmidt Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root ganglia Pharmacological Research Neuropathic pain Dorsal root ganglia Pediatric Proteomics MEFISTO Systems pharmacology |
| title | Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root ganglia |
| title_full | Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root ganglia |
| title_fullStr | Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root ganglia |
| title_full_unstemmed | Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root ganglia |
| title_short | Deep proteomics and network pharmacology reveal sex- and age-shared neuropathic pain signatures in mouse dorsal root ganglia |
| title_sort | deep proteomics and network pharmacology reveal sex and age shared neuropathic pain signatures in mouse dorsal root ganglia |
| topic | Neuropathic pain Dorsal root ganglia Pediatric Proteomics MEFISTO Systems pharmacology |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824004973 |
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