Skip to main content

Advertisement

SpringerLink
Log in

UNC5B Overexpression Alleviates Peripheral Neuropathic Pain by Stimulating Netrin-1-Dependent Autophagic Flux in Schwann Cells

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Lesions or diseases of the somatosensory system can cause neuropathic pain (NP). Schwann cell (SC) autophagy plays an important role in NP. Uncoordinated gene 5 homolog B (UNC5B), the canonical dependent receptor of netrin-1, is known to be exclusively expressed in SCs and involved in NP; however, the underlying mechanisms were unclear. A rat model of sciatic nerve chronic constriction injury (CCI) was used to induce peripheral neuropathic pain. Adeno-associated virus (AAV) overexpressing UNC5B was applied to the injured nerve, and an autophagy inhibitor, 3-mechyladenine (3-MA), was intraperitoneally injected in some animals. Behavioral tests were performed to evaluate NP, the morphology of the injured nerves was analyzed, and autophagy-related proteins were detected. A rat SC line (RSC96) undergoing oxygen and glucose deprivation (OGD) was used to mimic an ischemic setting to examine the role of UNC5B in autophagy. Local UNC5B overexpression alleviated CCI-induced NP and rescued myelin degeneration. Meanwhile, UNC5B overexpression improved CCI-induced impairment of autophagic flux, while the autophagy inhibitor 3-MA reversed the analgesic effect of UNC5B. In cultured SCs, UNC5B helped recruit netrin-1 to the cell membrane. UNC5B overexpression promoted autophagic flux while inhibiting apoptosis, which was further augmented with exogenous netrin-1 and reversed by netrin-1 knockdown. The enhanced phosphorylation of AMP-activated protein kinase (AMPK) and Unc51-like autophagy activating kinase 1 (ULK1) by UNC5B overexpression was also correlated with netrin-1. Our results suggest that UNC5B facilitates autophagic flux in SCs via phosphorylation of AMPK and ULK1, dependent on its ligand netrin-1, protecting myelin and partly preventing injury-induced NP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

For data availability, please contact the corresponding author.

References

  1. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A et al (2017) Neuropathic pain Nat Rev Dis Primers 3:17002. https://doi.org/10.1038/nrdp.2017.2

    Article  PubMed  Google Scholar 

  2. Jensen TS, Baron R, Haanpää M, Kalso E, Loeser JD, Rice ASC, Treede R-D (2011) A new definition of neuropathic pain. Pain 152(10):2204–2205. https://doi.org/10.1016/j.pain.2011.06.017

    Article  PubMed  Google Scholar 

  3. Attal N, Lanteri-Minet M, Laurent B, Fermanian J, Bouhassira D (2011) The specific disease burden of neuropathic pain: results of a French nationwide survey. Pain 152(12):2836–2843. https://doi.org/10.1016/j.pain.2011.09.014

    Article  PubMed  Google Scholar 

  4. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N (2014) Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 155(4):654–662. https://doi.org/10.1016/j.pain.2013.11.013

    Article  PubMed  Google Scholar 

  5. Marinelli S, Nazio F, Tinari A, Ciarlo L, D’Amelio M, Pieroni L, Vacca V, Urbani A et al (2014) Schwann cell autophagy counteracts the onset and chronification of neuropathic pain. Pain 155(1). https://doi.org/10.1016/j.pain.2013.09.013

  6. Shen Y, Ding Z, Ma S, Ding Z, Zhang Y, Zou Y, Xu F, Yang X et al (2019) SETD7 mediates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury. Brain Behav Immun 82:382–395. https://doi.org/10.1016/j.bbi.2019.09.007

    Article  CAS  PubMed  Google Scholar 

  7. Su WF, Wu F, Jin ZH, Gu Y, Chen YT, Fei Y, Chen H, Wang YX et al (2019) Overexpression of P2X4 receptor in Schwann cells promotes motor and sensory functional recovery and remyelination via BDNF secretion after nerve injury. Glia 67(1):78–90. https://doi.org/10.1002/glia.23527

    Article  PubMed  Google Scholar 

  8. Beirowski B, Babetto E, Golden JP, Chen YJ, Yang K, Gross RW, Patti GJ, Milbrandt J (2014) Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance. Nat Neurosci 17(10):1351–1361. https://doi.org/10.1038/nn.3809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nave K-A (2010) Myelination and the trophic support of long axons. Nat Rev Neurosci 11(4):275–283. https://doi.org/10.1038/nrn2797

    Article  CAS  PubMed  Google Scholar 

  10. Nave K-A, Werner HB (2014) Myelination of the nervous system: mechanisms and functions. Annu Rev Cell Dev Biol 30:503–533. https://doi.org/10.1146/annurev-cellbio-100913-013101

    Article  CAS  PubMed  Google Scholar 

  11. Câmara CC, Araújo CV, de Sousa KKO, Brito GAC, Vale ML, Raposo RdS, Mendonça FE, Mietto BS et al (2015) Gabapentin attenuates neuropathic pain and improves nerve myelination after chronic sciatic constriction in rats. Neurosci Lett 607:52–58. https://doi.org/10.1016/j.neulet.2015.09.021

    Article  CAS  PubMed  Google Scholar 

  12. Gomez-Sanchez JA, Carty L, Iruarrizaga-Lejarreta M, Palomo-Irigoyen M, Varela-Rey M, Griffith M, Hantke J, Macias-Camara N et al (2015) Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves. J Cell Biol 210(1):153–168. https://doi.org/10.1083/jcb.201503019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42. https://doi.org/10.1016/j.cell.2007.12.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Levy JMM, Towers CG, Thorburn A (2017) Targeting autophagy in cancer. Nat Rev Cancer 17(9):528–542. https://doi.org/10.1038/nrc.2017.53

    Article  CAS  PubMed  Google Scholar 

  15. Menzies FM, Fleming A, Rubinsztein DC (2015) Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 16(6):345–357. https://doi.org/10.1038/nrn3961

    Article  CAS  PubMed  Google Scholar 

  16. Shi C-S, Shenderov K, Huang N-N, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH (2012) Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13(3):255–263. https://doi.org/10.1038/ni.2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cui M, Liang J, Xu D, Zhao L, Zhang X, Zhang L, Ren S, Liu D et al (2020) NLRP3 inflammasome is involved in nerve recovery after sciatic nerve injury. Int Immunopharmacol 84:106492. https://doi.org/10.1016/j.intimp.2020.106492

    Article  CAS  PubMed  Google Scholar 

  18. Jang SY, Yoon B-A, Shin YK, Yun SH, Jo YR, Choi YY, Ahn M, Shin T et al (2017) Schwann cell dedifferentiation-associated demyelination leads to exocytotic myelin clearance in inflammatory segmental demyelination. Glia 65(11):1848–1862. https://doi.org/10.1002/glia.23200

    Article  PubMed  Google Scholar 

  19. Dun XP, Parkinson DB (2017) Role of netrin-1 signaling in nerve regeneration. Int J Mol Sci 18:3. https://doi.org/10.3390/ijms18030491

    Article  CAS  Google Scholar 

  20. Wu S, Guo X, Zhou J, Zhu X, Zhang K, Lu Y, Chen Y (2020) High expression of UNC5B enhances tumor proliferation, increases metastasis, and worsens prognosis in breast cancer. Aging (Albany NY) 12(17):17079–17098. https://doi.org/10.18632/aging.103639

    Article  CAS  Google Scholar 

  21. Ranganathan P, Jayakumar C, Navankasattusas S, Li DY, Kim IM, Ramesh G (2014) UNC5B receptor deletion exacerbates tissue injury in response to AKI. J Am Soc Nephrol 25(2):239–249. https://doi.org/10.1681/asn.2013040418

    Article  CAS  PubMed  Google Scholar 

  22. Huang Y, Zhang Z, Miao M, Kong C (2021) The intracellular domain of UNC5B facilities proliferation and metastasis of bladder cancer cells. J Cell Mol Med 25(4):2121–2135. https://doi.org/10.1111/jcmm.16172

    Article  CAS  PubMed  Google Scholar 

  23. Ahn EH, Kang SS, Qi Q, Liu X, Ye K (2020) Netrin1 deficiency activates MST1 via UNC5B receptor, promoting dopaminergic apoptosis in Parkinson’s disease. Proc Natl Acad Sci U S A 117(39):24503–24513. https://doi.org/10.1073/pnas.2004087117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee HK, Seo IA, Seo E, Seo S-Y, Lee HJ, Park HT (2007) Netrin-1 induces proliferation of Schwann cells through Unc5b receptor. Biochem Biophys Res Commun 362(4):1057–1062

    Article  CAS  Google Scholar 

  25. Webber CA, Christie KJ, Cheng C, Martinez JA, Singh B, Singh V, Thomas D, Zochodne DW (2011) Schwann cells direct peripheral nerve regeneration through the Netrin-1 receptors, DCC and Unc5H2. Glia 59(10):1503–1517. https://doi.org/10.1002/glia.21194

    Article  PubMed  Google Scholar 

  26. JY Chen Z Huang PY Xiao J Yu SJ Liao 2020 Local uncoordinated gene 5H2 contributes to nerve injury-induced mechanical allodynia associated to its role in autophagy ClinExp Pharmacol Physiol https://doi.org/10.1111/1440-1681.13430

  27. Madison RD, Zomorodi A, Robinson GA (2000) Netrin-1 and peripheral nerve regeneration in the adult rat. Exp Neurol 161(2):563–570

    Article  CAS  Google Scholar 

  28. Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33 (1)

  29. Strappe PM, Hampton DW, Cachon-Gonzalez B, Fawcett JW, Lever A (2005) Delivery of a lentiviral vector in a Pluronic F127 gel to cells of the central nervous system. Eur J Pharm Biopharm 61(3):126–133. https://doi.org/10.1016/j.ejpb.2005.06.006

    Article  CAS  PubMed  Google Scholar 

  30. Wu H-F, Cen J-S, Zhong Q, Chen L, Wang J, Deng DYB, Wan Y (2013) The promotion of functional recovery and nerve regeneration after spinal cord injury by lentiviral vectors encoding Lingo-1 shRNA delivered by Pluronic F-127. Biomaterials 34(6):1686–1700. https://doi.org/10.1016/j.biomaterials.2012.11.013

    Article  CAS  PubMed  Google Scholar 

  31. Deuis JR, Dvorakova LS, Vetter I (2017) Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci 10:284. https://doi.org/10.3389/fnmol.2017.00284

    Article  PubMed  PubMed Central  Google Scholar 

  32. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63

    Article  CAS  Google Scholar 

  33. Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32(1):77–88. https://doi.org/10.1016/0304-3959(88)90026-7

    Article  CAS  PubMed  Google Scholar 

  34. Miyamoto Y, Torii T, Tago K, Tanoue A, Takashima S, Yamauchi J (2018) BIG1/Arfgef1 and Arf1 regulate the initiation of myelination by Schwann cells in mice. Sci Adv 4 (4):eaar4471. https://doi.org/10.1126/sciadv.aar4471

  35. Pawelec KM, Yoon C, Giger RJ, Sakamoto J (2019) Engineering a platform for nerve regeneration with direct application to nerve repair technology. Biomaterials 216:119263. https://doi.org/10.1016/j.biomaterials.2019.119263

    Article  CAS  PubMed  Google Scholar 

  36. Gaudet AD, Popovich PG, Ramer MS (2011) Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 8:110. https://doi.org/10.1186/1742-2094-8-110

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lim E-MF, Hoghooghi V, Hagen KM, Kapoor K, Frederick A, Finlay TM, Ousman SS (2021) Presence and activation of pro-inflammatory macrophages are associated with CRYAB expression in vitro and after peripheral nerve injury. J Neuroinflammation 18(1):82. https://doi.org/10.1186/s12974-021-02108-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Grilo AL, Mantalaris A (2019) Apoptosis: a mammalian cell bioprocessing perspective. Biotechnol Adv 37(3):459–475. https://doi.org/10.1016/j.biotechadv.2019.02.012

    Article  CAS  PubMed  Google Scholar 

  39. Herzig S, Shaw RJ (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19(2):121–135. https://doi.org/10.1038/nrm.2017.95

    Article  CAS  PubMed  Google Scholar 

  40. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A et al (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331(6016):456–461. https://doi.org/10.1126/science.1196371

    Article  CAS  PubMed  Google Scholar 

  41. Jaggi AS, Jain V, Singh N (2011) Animal models of neuropathic pain. Fundam Clin Pharmacol 25 (1). https://doi.org/10.1111/j.1472-8206.2009.00801.x

  42. Bhat SA, Gurtoo S, Deolankar SC, Fazili KM, Advani J, Shetty R, Prasad TSK, Andrabi S, Subbannayya Y (2019) A network map of netrin receptor UNC5B-mediated signaling. J Cell Commun Signal 13(1):121–127. https://doi.org/10.1007/s12079-018-0485-z

    Article  PubMed  Google Scholar 

  43. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH et al. (2021) Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy 17 (1). https://doi.org/10.1080/15548627.2020.1797280

  44. Hayano Y, Takasu K, Koyama Y, Yamada M, Ogawa K, Minami K, Asaki T, Kitada K et al (2016) Dorsal horn interneuron-derived netrin-4 contributes to spinal sensitization in chronic pain via Unc5B. J Exp Med 213(13):2949–2966

    Article  CAS  Google Scholar 

  45. Truini A, Garcia-Larrea L, Cruccu G (2013) Reappraising neuropathic pain in humans–how symptoms help disclose mechanisms. Nat Rev Neurol 9(10):572–582. https://doi.org/10.1038/nrneurol.2013.180

    Article  CAS  PubMed  Google Scholar 

  46. O’Connor AB, Schwid SR, Herrmann DN, Markman JD, Dworkin RH (2008) Pain associated with multiple sclerosis: systematic review and proposed classification. Pain 137 (1). https://doi.org/10.1016/j.pain.2007.08.024

  47. Hong S, Remacle AG, Shiryaev SA, Choi W, Hullugundi SK, Dolkas J, Angert M, Nishihara T et al (2017) Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain. Brain Behav Immun 60:282–292. https://doi.org/10.1016/j.bbi.2016.11.003

    Article  CAS  PubMed  Google Scholar 

  48. Koike H, Iijima M, Mori K, Yamamoto M, Hattori N, Watanabe H, Tanaka F, Doyu M, Sobue G (2008) Neuropathic pain correlates with myelinated fibre loss and cytokine profile in POEMS syndrome. J Neurol Neurosurg Psychiatry 79(10):1171–1179. https://doi.org/10.1136/jnnp.2007.135681

    Article  CAS  PubMed  Google Scholar 

  49. Shubayev VI, Strongin AY, Yaksh TL (2016) Role of myelin auto-antigens in pain: a female connection. Neural Regen Res 11(6):890–891. https://doi.org/10.4103/1673-5374.184452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen JTC, Schmidt L, Schürger C, Hankir MK, Krug SM, Rittner HL (2021) Netrin-1 as a multitarget barrier stabilizer in the peripheral nerve after injury. Int J Mol Sci 22 (18). https://doi.org/10.3390/ijms221810090

  51. Salzer JL (2015) Schwann cell myelination. Cold Spring Harb Perspect Biol 7(8):a020529. https://doi.org/10.1101/cshperspect.a020529

    Article  PubMed  PubMed Central  Google Scholar 

  52. Arthur-Farraj PJ, Latouche M, Wilton DK, Quintes S, Chabrol E, Banerjee A, Woodhoo A, Jenkins B et al (2012) c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 75(4):633–647. https://doi.org/10.1016/j.neuron.2012.06.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Poplawski G, Ishikawa T, Brifault C, Lee-Kubli C, Regestam R, Henry KW, Shiga Y, Kwon H et al (2018) Schwann cells regulate sensory neuron gene expression before and after peripheral nerve injury. Glia 66(8):1577–1590. https://doi.org/10.1002/glia.23325

    Article  PubMed  PubMed Central  Google Scholar 

  54. Li R, Li D, Wu C, Ye L, Wu Y, Yuan Y, Yang S, Xie L et al (2020) Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration. Theranostics 10(4):1649–1677. https://doi.org/10.7150/thno.40919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brosius Lutz A, Chung W-S, Sloan SA, Carson GA, Zhou L, Lovelett E, Posada S, Zuchero JB, Barres BA (2017) Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury. Proc Natl Acad Sci USA 114(38):E8072–E8080. https://doi.org/10.1073/pnas.1710566114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ogura K-I, Goshima Y (2006) The autophagy-related kinase UNC-51 and its binding partner UNC-14 regulate the subcellular localization of the Netrin receptor UNC-5 in Caenorhabditis elegans. Development (Cambridge, England) 133(17):3441–3450

    Article  CAS  Google Scholar 

  57. Kim J, Kundu M, Viollet B, Guan K-L (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141. https://doi.org/10.1038/ncb2152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jang JE, Eom J-I, Jeung H-K, Cheong J-W, Lee JY, Kim JS, Min YH (2017) AMPK-ULK1-mediated autophagy confers resistance to BET inhibitor JQ1 in acute myeloid Leukemia stem cells. Clin cancer res :official j American Assoc Cancer Res 23(11):2781–2794. https://doi.org/10.1158/1078-0432.CCR-16-1903

    Article  CAS  Google Scholar 

  59. Bai L, Mei X, Shen Z, Bi Y, Yuan Y, Guo Z, Wang H, Zhao H et al (2017) Netrin-1 improves functional recovery through autophagy regulation by activating the AMPK/mTOR signaling pathway in rats with spinal cord injury. Sci Rep 7:42288. https://doi.org/10.1038/srep42288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Guenebeaud C, Goldschneider D, Castets M, Guix C, Chazot G, Delloye-Bourgeois C, Eisenberg-Lerner A, Shohat G et al (2010) The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. Mol Cell 40(6):863–876. https://doi.org/10.1016/j.molcel.2010.11.021

    Article  CAS  PubMed  Google Scholar 

  61. Li J, Wang G, Weng Y, Ding M, Yu W (2020) Netrin-1 contributes to peripheral nerve injury induced neuropathic pain via regulating phosphatidylinositol 4-kinase IIa in the spinal cord dorsal horn in mice. Neurosci Lett 735:135161. https://doi.org/10.1016/j.neulet.2020.135161

    Article  CAS  PubMed  Google Scholar 

  62. Ding S, Guo X, Zhu L, Wang J, Li T, Yu Q, Zhang X (2021) Macrophage-derived netrin-1 contributes to endometriosis-associated pain. Ann Transl Med 9(1):29. https://doi.org/10.21037/atm-20-2161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wu CH, Yuan XC, Gao F, Li HP, Cao J, Liu YS, Yu W, Tian B et al (2016) Netrin-1 contributes to myelinated afferent fiber sprouting and neuropathic pain. Mol Neurobiol 53(8):5640–5651. https://doi.org/10.1007/s12035-015-9482-x

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Scientific Foundation of China, (82071366), Natural Scientific Foundation of Guangdong, China (2019A1515011600), grants from Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases (2020B1212060017), Guangdong Provincial Clinical Research Center for Neurological Diseases (2020B1111170002), Southern China International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases (2015B050501003 and 2020A0505020004), Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, and Guangzhou Clinical Research and Translational Center for Major Neurological Diseases (201604020010).

Author information

Authors and Affiliations

  1. Department of Neurology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou, 510080, China

    Pei-yao Xiao, Jing-yan Chen, Qing Zeng, Zi Huang, Bei-xu Huang, Jian Yu & Song-jie Liao

  2. Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, No. 58 Zhongshan Road 2, Guangzhou, 510080, China

    Pei-yao Xiao, Jing-yan Chen, Qing Zeng, Zi Huang, Bei-xu Huang, Jian Yu & Song-jie Liao

  3. Guangzhou First People’s Hospital, No.1 Panfu Road, Guangzhou, 510180, China

    Jing-yan Chen

Authors
  1. Pei-yao Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing-yan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bei-xu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jian Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Song-jie Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Peiyao Xiao and Jingyan Chen completed the experiments and wrote the manuscript. Qing Zeng participated in the animal experiments. Zi Huang did some in vitro experiments. Beixu Huang did some image analysis. Songjie Liao and Jian Yu designed and funded the whole study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jian Yu or Song-jie Liao.

Ethics declarations

Ethics Approval

The animal use protocol has been reviewed and approved by the Institutional Animal Care and Use Committee (IACUC), Sun Yat-Sen University (SYSU-IACUC-2021–000571).

Consent to Participate

Not applicable.

Consent for Publication

All authors have seen and approved the manuscript and contributed significantly to this work.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 397 KB)

Supplementary file2 (PDF 80 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, Py., Chen, Jy., Zeng, Q. et al. UNC5B Overexpression Alleviates Peripheral Neuropathic Pain by Stimulating Netrin-1-Dependent Autophagic Flux in Schwann Cells. Mol Neurobiol 59, 5041–5055 (2022). https://doi.org/10.1007/s12035-022-02861-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-02861-z

Keywords

Search

Navigation