Targeting the PDK1/c‐Myc/SOX10 Signaling in Oligodendrocytes Alleviates Neuropathic Pain
Source abstract
Abstract
ABSTRACT Neuropathic pain (NPP) is a critical clinical challenge with limited therapeutic options. While neuronal mechanisms have been extensively studied, the contribution of oligodendrocyte (OL) homeostasis to NPP pathogenesis is poorly understood. Here, we show that chronic constriction injury (CCI) causes demyelination and downregulation of 3‐phosphoinositide‐dependent kinase 1 (PDK1) in the central nervous system (CNS) in mice. Functional analysis of inducible OL lineage‐specific Pdk1 conditional knockout ( Pdk1 cKO) mice reveals mechanical allodynia and thermal hyperalgesia, a pattern of sensory changes that closely resembles NPP in CCI mice. RNA sequencing (RNA‐seq), morphological, and molecular analyses demonstrate that PDK1 deficiency impairs myelination via the c‐Myc/SOX10 axis. Notably, pharmacological enhancement of remyelination or AAV‐mediated knockdown of c‐Myc restores nodal integrity and alleviates NPP in Pdk1 cKO mice. Our findings establish PDK1‐mediated OL homeostasis as a critical determinant of NPP pathogenesis and identify c‐Myc modulation as a novel therapeutic strategy for NPP.
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Research context
OpenAlex topics: Neurogenesis and neuroplasticity mechanisms · Pain Mechanisms and Treatments · Nerve injury and regeneration
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
State Key Laboratory of Pharmaceutical Biotechnology Department of Neurosurgery Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Jiangsu Key Laboratory of Molecular Medicine Model Animal Research Center Medical School Nanjing University Nanjing China
Co‐innovation Center of Neuroregeneration Nantong University Nantong China
Department of Laser Surgery Hospital of Dermatology Chinese Academy of Medical Sciences and Peking Union Medical College Nanjing China
Department of Anesthesiology and Perioperative Medicine The First Affiliated Hospital of Nanjing Medical University Nanjing China
Department of Anesthesiology Pain and Perioperative Medicine The First Affiliated Hospital of Zhengzhou University Zhengzhou China
Department of Anesthesiology Hospital of Dermatology Chinese Academy of Medical Sciences and Peking Union Medical College Nanjing China
Funding
National Natural Science Foundation of China
References (58)
Show source-provided references
1. 10.1016/j.pain.2011.06.01710.1016/j.pain.2011.06.017 ↗
2. 10.1016/j.lpm.2024.10423210.1016/j.lpm.2024.104232 ↗
3. 10.1038/s41593‐024‐01642‐210.1038/s41593‐024‐01642‐2 ↗
4. 10.7554/eLife.2332910.7554/eLife.23329 ↗
5. 10.1111/jnc.1620610.1111/jnc.16206 ↗
6. 10.1038/cdd.2016.8410.1038/cdd.2016.84 ↗
7. 10.1186/s13041‐020‐00604‐610.1186/s13041‐020‐00604‐6 ↗
8. 10.1093/cercor/bhab42810.1093/cercor/bhab428 ↗
9. 10.3390/biomedicines1012317110.3390/biomedicines10123171 ↗
10. 10.3389/fncel.2017.0033010.3389/fncel.2017.00330 ↗
11. 10.1523/JNEUROSCI.2496‐19.202010.1523/JNEUROSCI.2496‐19.2020 ↗
12. 10.1128/MCB.00230‐1610.1128/MCB.00230‐16 ↗
13. 10.1016/0304‐3959(88)90209‐610.1016/0304‐3959(88)90209‐6 ↗
14. 10.1523/JNEUROSCI.2455‐19.202110.1523/JNEUROSCI.2455‐19.2021 ↗
15. 10.1523/JNEUROSCI.2146-22.202310.1523/JNEUROSCI.2146-22.2023 ↗
16. The Role of Oligodendrocytes in Chronic Pain: Cellular and Molecular Mechanisms
17. 10.1016/j.biologicals.2016.03.00510.1016/j.biologicals.2016.03.005 ↗
18. 10.1016/j.nbd.2020.10521210.1016/j.nbd.2020.105212 ↗
19. 10.1002/glia.2264810.1002/glia.22648 ↗
20. 10.1016/j.ebiom.2021.10375610.1016/j.ebiom.2021.103756 ↗
21. 10.1016/j.neuroscience.2014.01.05110.1016/j.neuroscience.2014.01.051 ↗
22. 10.1016/j.phymed.2023.15527610.1016/j.phymed.2023.155276 ↗
23. 10.1016/j.clinph.2008.03.01610.1016/j.clinph.2008.03.016 ↗
24. 10.1210/en.2014‐115810.1210/en.2014‐1158 ↗
25. 10.1111/cns.1375110.1111/cns.13751 ↗
26. 10.1523/JNEUROSCI.3296‐08.200810.1523/JNEUROSCI.3296‐08.2008 ↗
27. 10.1038/nm.361810.1038/nm.3618 ↗
28. 10.1097/ALN.000000000000213010.1097/ALN.0000000000002130 ↗
29. 10.1007/s13311‐020‐00905‐710.1007/s13311‐020‐00905‐7 ↗
30. 10.3389/fnana.2025.155721410.3389/fnana.2025.1557214 ↗
31. 10.1186/s12974‐024‐03207‐310.1186/s12974‐024‐03207‐3 ↗
32. 10.1093/brain/awac30710.1093/brain/awac307 ↗
33. 10.1073/pnas.141909911210.1073/pnas.1419099112 ↗
34. 10.3389/fncel.2018.0039910.3389/fncel.2018.00399 ↗
35. 10.2174/138161282266615120400063610.2174/1381612822666151204000636 ↗
36. 10.1038/ncomms647210.1038/ncomms6472 ↗
37. 10.1093/cercor/bhz14610.1093/cercor/bhz146 ↗
38. 10.1038/nrn202310.1038/nrn2023 ↗
39. 10.1038/s41467‐019‐14154‐610.1038/s41467‐019‐14154‐6 ↗
40. 10.1038/s41467‐025‐59849‐110.1038/s41467‐025‐59849‐1 ↗
41. 10.1177/030006052090365310.1177/0300060520903653 ↗
42. 10.1002/glia.2356910.1002/glia.23569 ↗
43. 10.1371/journal.pgen.100390710.1371/journal.pgen.1003907 ↗
44. 10.7150/ijbs.7367310.7150/ijbs.73673 ↗
45. 10.1038/nn.339010.1038/nn.3390 ↗
46. 10.1002/glia.7008210.1002/glia.70082 ↗
47. 10.1073/pnas.240365212110.1073/pnas.2403652121 ↗
48. 10.1073/pnas.040273310110.1073/pnas.0402733101 ↗
49. 10.1002/dvg.2033510.1002/dvg.20335 ↗
50. 10.1016/j.pneurobio.2023.10243610.1016/j.pneurobio.2023.102436 ↗
51. 10.1016/j.phymed.2019.15316610.1016/j.phymed.2019.153166 ↗
52. 10.1146/annurev.pa.20.040180.00230110.1146/annurev.pa.20.040180.002301 ↗
53. 10.1097/j.pain.000000000000017210.1097/j.pain.0000000000000172 ↗
54. 10.1038/s41586‐022‐04860‐510.1038/s41586‐022‐04860‐5 ↗
55. 10.7150/thno.7214410.7150/thno.72144 ↗
56. Stereotaxic Injection of a Viral Vector for Conditional Gene Manipulation in the Mouse Spinal Cord
57. Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin‐Induced Spinal Cord Demyelination in Mice
58. 10.1186/s13046‐024‐03230‐510.1186/s13046‐024‐03230‐5 ↗