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Axonal Regeneration Mediated by a Novel Axonal Guidance Pair, Galectin-1 and Secernin-1

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Abstract

Galectin-1 (Gal-1), a member of the Galectin family, is expressed in various tissues and responsible for multiple biological activities. Previous studies reported that extracellular Gal-1 participated in axonal growth and repair, and Gal-1 knockout mice exhibited memory impairment. However, no study has demonstrated the direct contribution of intracellular Gal-1 upregulation in neurons to promoting axonal regeneration in the brain and recovering memory function. In the present study, we found that axonal growth is promoted by overexpression of Gal-1 via adeno-associated virus serotype 9 delivery in primary cultured hippocampal neurons. Moreover, Gal-1 was expressed on the membranes of growth cones in hippocampal neurons and interacted with a novel axonal guidance molecule, Secernin-1, which was secreted from prefrontal cortex (PFC) neurons. Gal-1-overexpression-driven axonal growth was enhanced when recombinant (extracellular) Secernin-1 was treated to the axonal site in a neuron device chamber. Direct binding of extracellular Secernin-1 with Gal-1 was detected through immunoprecipitation and immunocytochemistry, demonstrating that Gal-1 possibly works as an axonal guidance receptor for Secernin-1 in hippocampal neurons. In the PFC, the expression of Gal-1 in axonal shafts and terminals of hippocampal neurons was decreased in the 5XFAD mouse model of Alzheimer’s disease (AD). Overexpression of Gal-1 in hippocampal neurons recovered memory deficits and induced axonal regeneration toward the PFC in 5XFAD mice. This study suggests that the enhanced interaction of Secernin-1 and Gal-1 can be harnessed as a therapeutic strategy for long-distance and direction-specific axonal regeneration in AD.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Camby I, Le Mercier M, Lefranc F, Kiss R (2006) Galectin-1: a small protein with major functions. Glycobiology 16:137R-157R. https://doi.org/10.1093/glycob/cwl025

    Article  CAS  Google Scholar 

  2. Horie H, Inagaki Y, Sohma Y, Nozawa R, Okawa K, Hasegawa M et al (1999) Galectin-1 regulates initial axonal growth in peripheral nerves after axotomy. J Neurosci 19:9964–9974. https://doi.org/10.1523/JNEUROSCI.19-22-09964.1999

    Article  CAS  Google Scholar 

  3. McGraw J, McPhail LT, Oschipok LW, Horie H, Poirier F, Steeves JD et al (2004) Galectin-1 in regenerating motorneurons. Eur J Neurosci 20:2872–2880. https://doi.org/10.1111/j.1460-9568.2004.03802.x

    Article  CAS  Google Scholar 

  4. Horie H, Kadoya T, Hikawa N, Sango K, Inoue H, Takeshita K et al (2004) Oxidized galectin-1 stimulates macrophages to promote axonal regeneration in peripheral nerves after axotomy. J Neurosci 24:1873–1880. https://doi.org/10.1523/JNEUROSCI.4483-03.2004

    Article  CAS  Google Scholar 

  5. Barondes SH, Castronovo V, Cooper DN, Cummings RD, Drickamer K, Feizi T et al (1994) Galectins: a family of animal beta-galactoside-binding lectins. Cell 76:597–598. https://doi.org/10.1016/0092-8674(94)90498-7

    Article  CAS  Google Scholar 

  6. Mahanthappa NK, Cooper DN, Barondes SH, Schwarting GA (1994) Rat olfactory neurons can utilize the endogenous lectin, L-14, in a novel adhesion mechanism. Development 120:1373–1384. https://doi.org/10.1242/dev.120.6.1373

    Article  CAS  Google Scholar 

  7. Puche AC, Poirier F, Hai M, Bartlett PF, Key B (1996) Role of galectin-1 in the developing mouse olfactory system. Dev Biol 179:274–287. https://doi.org/10.1006/dbio.1996.0257

    Article  CAS  Google Scholar 

  8. Tenne-Brown J, Puche AC, Key B (1998) Expression of galectin-1 in the mouse olfactory system. Int J Dev Biol 42:791–799

    CAS  Google Scholar 

  9. Quintá HR, Pasquini JM, Rabinovich GA, Pasquini LA (2014) Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury. Cell Death Differ 21:941–955. https://doi.org/10.1038/cdd.2014.14

    Article  CAS  Google Scholar 

  10. Gaudet AD, Sweet DR, Polinski NK, Guan Z, Popovich PG (2015) Galectin-1 in injured rat spinal cord: implications for macrophage phagocytosis and neural repair. Mol Cell Neurosci 64:84–94. https://doi.org/10.1016/j.mcn.2014.12.006

    Article  CAS  Google Scholar 

  11. Wu G, Lu ZH, André S, Gabius HJ, Ledeen RW (2016) Functional interplay between ganglioside GM1 and cross-linking galectin-1 induces axon-like neuritogenesis via integrin-based signaling and TRPC5-dependent Ca2+ influx. J Neurochem 136:550–563. https://doi.org/10.1111/jnc.13418

    Article  CAS  Google Scholar 

  12. Kajitani K, Kobayakawa Y, Nomaru H, Kadoya T, Horie H, Nakabeppu Y (2014) Characterization of galectin-1-positive cells in the mouse hippocampus. NeuroReport 25:171–176. https://doi.org/10.1097/WNR.0000000000000068

    Article  CAS  Google Scholar 

  13. Quintá HR, Wilson C, Blidner AG, González-Billault C, Pasquini LA, Rabinovich GA et al (2016) Ligand-mediated galectin-1 endocytosis prevents intraneural H2O2 production promoting F-actin dynamics reactivation and axonal re-growth. Exp Neurol 283:165–178. https://doi.org/10.1016/j.expneurol.2016.06.009

    Article  CAS  Google Scholar 

  14. Sakaguchi M, Arruda-Carvalho M, Kang NH, Imaizumi Y, Poirier F, Okano H et al (2011) Impaired spatial and contextual memory formation in galectin-1 deficient mice. Mol Brain 4:33. https://doi.org/10.1186/1756-6606-4-33

    Article  CAS  Google Scholar 

  15. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J et al (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140. https://doi.org/10.1523/JNEUROSCI.1202-06.2006

    Article  CAS  Google Scholar 

  16. Tohda C, Urano T, Umezaki M, Nemere I, Kuboyama T (2012) Diosgenin is an exogenous activator of 1,25D3-MARRS/Pdia3/ERp57 and improves Alzheimer’s disease pathologies in 5XFAD mice. Sci Rep 2:535. https://doi.org/10.1038/srep00535

    Article  CAS  Google Scholar 

  17. Yang X, Nomoto K, Tohda C (2021) Diosgenin content is a novel criterion to assess memory enhancement effect of yam extracts. J Nat Med 75:207–216. https://doi.org/10.1007/s11418-020-01451-4

    Article  CAS  Google Scholar 

  18. Yang X, Tohda C (2018) Diosgenin restores Aβ-induced axonal degeneration by reducing the expression of heat shock cognate 70 (HSC70). Sci Rep 8:11707. https://doi.org/10.1038/s41598-018-30102-8

    Article  CAS  Google Scholar 

  19. Yang X, Tohda C (2018) Heat shock cognate 70 inhibitor, VER-155008, reduces memory deficits and axonal degeneration in a mouse model of Alzheimer’s disease. Front Pharmacol 9:48.https://doi.org/10.3389/fphar.2018.00048

  20. Bojic-Trbojevic Ž, Jovanovic Krivokuca M, Stefanoska I, Kolundžic N, Vilotic A, Kadoya T et al (2018) Integrin β1 is bound to galectin-1 in human trophoblast. J Biochem 163:39–50. https://doi.org/10.1093/jb/mvx061

    Article  CAS  Google Scholar 

  21. Wang C, Furlong TM, Stratton PG, Lee C, Xu L, Merlin S et al (2021) Hippocampus-prefrontal coupling regulates recognition memory for novelty discrimination. J Neurosci 41:9617–9632. https://doi.org/10.1523/JNEUROSCI.1202-21.2021

    Article  CAS  Google Scholar 

  22. Oh SW, Harris JA, Ng L, Winslow B, Cain N, Mihalas S et al (2014) A mesoscale connectome of the mouse brain. Nature 508:207–214. https://doi.org/10.1038/nature13186

    Article  CAS  Google Scholar 

  23. Li S, Overman JJ, Katsman D, Kozlov SV, Donnelly CJ, Twiss JL et al (2010) An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nat Neurosci 13:1496–1504. https://doi.org/10.1038/nn.2674

    Article  CAS  Google Scholar 

  24. Way G, Morrice N, Smythe C, O’Sullivan AJ (2002) Purification and identification of Secernin, a novel cytosolic protein that regulates exocytosis in mast cells. Mol Biol Cell 13:3344–3354. https://doi.org/10.1091/mbc.e01-10-0094

    Article  CAS  Google Scholar 

  25. Lindhout FW, Cao Y, Kevenaar JT, Bodzęta A, Stucchi R, Boumpoutsari MM et al (2019) VAP-SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function. EMBO J 38:e101345. https://doi.org/10.15252/embj.2018101345

    Article  CAS  Google Scholar 

  26. Drummond E, Wisniewski T (2017) The use of localized proteomics to identify the drivers of Alzheimer’s disease pathogenesis. Neural Regen Res 12:912–913. https://doi.org/10.4103/1673-5374.208570

    Article  CAS  Google Scholar 

  27. Pires G, McElligott S, Drusinsky S, Halliday G, Potier MC, Wisniewski T et al (2019) Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer’s disease and not in other tauopathies. Acta Neuropathol Commun 7:195. https://doi.org/10.1186/s40478-019-0848-6

    Article  CAS  Google Scholar 

  28. He Z, Jin Y (2016) Intrinsic control of axon regeneration. Neuron 90(3):437–451

    Article  CAS  Google Scholar 

  29. Blazquez-Llorca L, Valero-Freitag S, Rodrigues EF, Merchán-Pérez Á, Rodríguez JR, Dorostkar MM et al (2017) High plasticity of axonal pathology in Alzheimer’s disease mouse models. Acta Neuropathol Commun 5:14. https://doi.org/10.1186/s40478-017-0415-y

    Article  CAS  Google Scholar 

  30. Jin Y, Dougherty SE, Wood K, Sun L, Cudmore RH, Abdalla A et al (2016) Regrowth of serotonin axons in the adult mouse brain following injury. Neuron 91:748–762. https://doi.org/10.1016/j.neuron.2016.07.024

    Article  CAS  Google Scholar 

  31. Takaku S, Yanagisawa H, Watabe K, Horie H, Kadoya T, Sakumi K et al (2013) GDNF promotes neurite outgrowth and upregulates galectin-1 through the RET/PI3K signaling in cultured adult rat dorsal root ganglion neurons. Neurochem Int 62:330–339. https://doi.org/10.1016/j.neuint.2013.01.008

    Article  CAS  Google Scholar 

  32. Delbrouck C, Doyen I, Belot N, Decaestecker C, Ghanooni R, de Lavareille A et al (2002) Galectin-1 is overexpressed in nasal polyps under budesonide and inhibits eosinophil migration. Lab Invest 82:147–158. https://doi.org/10.1038/labinvest.3780407

    Article  CAS  Google Scholar 

  33. Choe YS, Shim C, Choi D, Lee CS, Lee KK, Kim K (1997) Expression of galectin-1 mRNA in the mouse uterus is under the control of ovarian steroids during blastocyst implantation. Mol Reprod Dev 48:261–266. https://doi.org/10.1002/(SICI)1098-2795(199710)48:2%3c261::AID-MRD14%3e3.0.CO;2-0

    Article  CAS  Google Scholar 

  34. Lu Y, Lotan D, Lotan R (2000) Differential regulation of constitutive and retinoic acid-induced galectin-1 gene transcription in murine embryonal carcinoma and myoblastic cells. Biochim Biophys Acta 1491:13–19. https://doi.org/10.1016/s0167-4781(00)00055-5

    Article  CAS  Google Scholar 

  35. Ohannesian DW, Lotan D, Lotan R (1994) Concomitant increases in galectin-1 and its glycoconjugate ligands (carcinoembryonic antigen, lamp-1, and lamp-2) in cultured human colon carcinoma cells by sodium butyrate. Cancer Res 54:5992–6000

    CAS  Google Scholar 

  36. Kultima K, Nyström AM, Scholz B, Gustafson AL, Dencker L, Stigson M (2004) Valproic acid teratogenicity: a toxicogenomics approach. Environ Health Perspect 112:1225–1235. https://doi.org/10.1289/txg.7034

    Article  CAS  Google Scholar 

  37. Akazawa C, Nakamura Y, Sango K, Horie H, Kohsaka S (2004) Distribution of the galectin-1 mRNA in the rat nervous system: its transient upregulation in rat facial motor neurons after facial nerve axotomy. Neuroscience 125:171–178. https://doi.org/10.1016/j.neuroscience.2004.01.034

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Editage (www.editage.jp) for English language editing. Moreover, we would like to thank the support of the 2021 Director Leadership Expenses, Institute of Natural Medicine, University of Toyama.

Funding

This work was funded by JSPS KAKENHI, Grant Number 19K16288 (X. Y.), a grant for young researcher of Hokuriku Bank, LTD (X. Y.), a grant from the Research Center for Idling Brain Science (X. Y.), a foundation from Tamura Science Technology (X. Y.), Grant-in-Aid for a Cooperative Research Project from the Institute of Natural Medicine at the University of Toyama in 2017–2020 (C. T.), and the Discretionary Funds of the President of the University of Toyama (C. T.). The funding bodies were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

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  1. Section of Neuromedical Science, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Ximeng Yang & Chihiro Tohda

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X. Y. and C. T. designed the experiments and drafted the manuscript. X. Y. performed the experiments and analyzed the data. X. Y. and C. T. acquired funding.

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Correspondence to Chihiro Tohda.

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All experiments were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the University of Toyama. The Committee for Animal Care and Use at the Sugitani Campus of the University of Toyama approved the study protocol (approval number: A2020INM-1).

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Yang, X., Tohda, C. Axonal Regeneration Mediated by a Novel Axonal Guidance Pair, Galectin-1 and Secernin-1. Mol Neurobiol 60, 1250–1266 (2023). https://doi.org/10.1007/s12035-022-03125-6

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