Advertisement

Biochemistry (Moscow)

, Volume 84, Issue 9, pp 979–991 | Cite as

The Role of Plasminogen Activator System in the Pathogenesis of Epilepsy

  • A. A. Shmakova
  • K. A. Rubina
  • K. V. Anokhin
  • V. A. Tkachuk
  • E. V. SeminaEmail author
Review
  • 2 Downloads

Abstract

Neurodegenerative disorders and ischemic conditions leading to the development of Alzheimer’s and Parkinson’s diseases, vascular dementia, etc. have attracted attention of many researchers studying the mechanisms of abnormalities in the central nervous system (CNS). The genetic predisposition for these diseases has been reported in the studies of the last few decades. Current achievements in biochemistry and molecular biology have revealed the relationships between risk factors contributing to the development of these pathologies and target proteins controlled by the genome. It has been demonstrated that polymorphisms/mutations in the genes regulating the growth of axons and blood vessels, glia formation and neuronal migration can lead to the brain malformation and its distorted function in embryogenesis and early ontogenesis. Guidance receptors regulating axon growth and establishment of neuronal circuits and cognitive functions take the central role among the molecules involved in the development of neurodegenerative conditions and pathologies, such as epilepsy, schizophrenia, and autism spectrum disorders. Recently, an interest in the role of plasminogen activators in various physiological and pathological conditions in the CNS has noticeably increased. Our previous publications have established the role of these proteins in the regulation of growth rate, growth trajectory, and branching of axons. In this review, we summarize the published data on the mechanisms underlying the involvement of plasminogen activator system in pathological conditions in the brain with special emphasis on epilepsy.

Keywords

plasminogen activator system urokinase urokinase receptor tissue plasminogen activator brain epilepsy 

Abbreviations

BBB

blood-brain barrier

BDNF

brain-derived neurotrophic factor

CNS

central nervous system

ECM

extracellular matrix

EGFR

epidermal growth factor receptor

ERK

extracellular signal-regulated kinase

GABA

γ-amino-butyric acid

GPI

glycosylphosphatidylinositol

HGF

hepatocyte growth factor

LRP-1

low density lipoprotein receptor-related protein 1

NGF

nerve growth factor

p75NTR

p75 neurotrophin receptor

PAI

plasminogen activator inhibitor

PAS

plasminogen activator system

PDGFR-β

platelet growth factor receptor β

Plat

tissue plasminogen activator gene

Plau

urokinase gene

Plaur

urokinase receptor gene

tPA

tissue plasminogen activator

Trk

tropomyosin receptor kinase

uPA

urokinase

uPAR

urokinase receptor

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Funding. The study was supported by the Russian Science Foundation (project 19-75-30007; literature search and analysis, review writing and preparation) and Russian Foundation for Basic Research (project 17-04-00386; figure drawing and design with Adobe Illustrator CC 2017).

Compliance with ethical standards. This review does not contain any studies involving animals or human participants performed by any of the authors.

References

  1. 1.
    Pitkanen, A., Ndode-Ekane, X. E., Lukasiuk, K., Wilczynski, G. M., Dityatev, A., Walker, M. C., Chabrol, E., Dedeurwaerdere, S., Vazquez, N., and Powell, E. M. (2014) Neural ECM and epilepsy, Prog. Brain Res., 214, 229–262, doi:  https://doi.org/10.1016/B978-0-444-63486-3.00011-6.CrossRefPubMedGoogle Scholar
  2. 2.
    Semina, E., Rubina, K., Sysoeva, V., Rysenkova, K., Klimovich, P., Plekhanova, O., and Tkachuk, V. (2016) Urokinase and urokinase receptor participate in regulation of neuronal migration, axon growth and branching, Eur. J. Cell Biol., 95, 2950–310, doi:  https://doi.org/10.1016/j.ejcb.2016.05.003.Google Scholar
  3. 3.
    Merino, P., Diaz, A., Jeanneret, V., Wu, F., Torre, E., Cheng, L., and Yepes, M. (2017) Urokinase-type plasminogen activator (uPA) binding to the uPA receptor (uPAR) promotes axonal regeneration in the central nervous system, J. Biol. Chem., 292, 2741–2753, doi:  https://doi.org/10.1074/jbc.M116.761650.CrossRefPubMedGoogle Scholar
  4. 4.
    Bruneau, N., and Szepetowski, P. (2011) The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system, Curr. Pharm. Des., 17, 1914–1923, doi:  https://doi.org/10.2174/138161211796718198.CrossRefPubMedGoogle Scholar
  5. 5.
    Morales, D., McIntosh, T., Conte, V., Fujimoto, S., Graham, D., Grady, M. S., and Stein, S. C. (2006) Impaired fibrinolysis and traumatic brain injury in mice, J. Neurotrauma, 23, 976–984, doi:  https://doi.org/10.1089/neu.2006.23.976.CrossRefPubMedGoogle Scholar
  6. 6.
    Yepes, M. (2018) The plasminogen activation system promotes neurorepair in the ischemic brain, Curr. Drug Targets, 20, 953–959 doi:  https://doi.org/10.2174/1389450120666181211144550.CrossRefGoogle Scholar
  7. 7.
    Abramovici, S., and Bagic, A. (2016) Epidemiology of epilepsy, Handb. Clin. Neurol., 138, 159–171, doi:  https://doi.org/10.1016/B978-0-12-802973-2.00010-0.CrossRefPubMedGoogle Scholar
  8. 8.
    Avakyan, G. N. (2014) Epidemiology of epilepsy and optimized medicated therapy of focal epilepsy, Epilep. Paroksizm. Sost., 6 3–5.Google Scholar
  9. 9.
    Karlov, V. A. (2005) A science of epileptic system. A merit of the Russia-wide academic school, Epilep. Paroksizm. Sost., 9, 76–85.CrossRefGoogle Scholar
  10. 10.
    Kalinina, D. S., Ganina, O. R., Vol’nova, A. B., and Zhuravin, I. A. (2014) Pathological conditions in the brain: use of animal models for examining epilepsy, Zdorov’e - Osnova Chelovech. Potents.: Problemy Puti Ikh Resheniya, 1, 127–130.Google Scholar
  11. 11.
    Mehra, A., Ali, C., Parcq, J., Vivien, D., and Docagne, F. (2016) The plasminogen activation system in neuroinflammation, Biochim. Biophys. Acta, 1862, 395–402, doi:  https://doi.org/10.1016/j.bbadis.2015.10.011.CrossRefPubMedGoogle Scholar
  12. 12.
    Smith, H. W., and Marshall, C. J. (2010) Regulation of cell signalling by uPAR, Nat. Rev. Mol. Cell Biol., 11, 23–36, doi:  https://doi.org/10.1038/nrm2821.CrossRefPubMedGoogle Scholar
  13. 13.
    Blasi, F., and Carmeliet, P. (2002) uPAR: a versatile signalling orchestrator, Nat. Rev. Mol. Cell Biol., 3, 932–943, doi:  https://doi.org/10.1038/nrm977.CrossRefPubMedGoogle Scholar
  14. 14.
    Medcalf, R. L. (2017) Fibrinolysis: from blood to the brain, J. Thromb. Haemost., 15, 2089–2098, doi:  https://doi.org/10.1111/jth.13849.CrossRefPubMedGoogle Scholar
  15. 15.
    Baron, A., Montagne, A., Casse, F., Launay, S., Maubert, E., Ali, C., and Vivien, D. (2010) NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity, Cell Death Differ., 17, 860–871, doi:  https://doi.org/10.1038/cdd.2009.172.CrossRefPubMedGoogle Scholar
  16. 16.
    Fredriksson, L., Lawrence, D. A., and Medcalf, R. L. (2017) tPA modulation of the blood-brain barrier: a unifying explanation for the pleiotropic effects of tPA in the CNS, Semin. Thromb. Hemost., 43, 154–168, doi:  https://doi.org/10.1055/s-0036-1586229.PubMedGoogle Scholar
  17. 17.
    Shi, Y., Mantuano, E., Inoue, G., Campana, W. M., and Gonias, S. L. (2009) Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway, Sci. Signal., 2, ra18, doi:  https://doi.org/10.1126/scisignal.2000188.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Montuori, N., Carriero, M. V., Salzano, S., Rossi, G., and Ragno, P. (2002) The cleavage of the urokinase receptor regulates its multiple functions, J. Biol. Chem., 277, 46932–46939, doi:  https://doi.org/10.1074/jbc.M207494200.CrossRefPubMedGoogle Scholar
  19. 19.
    Qian, Z., Gilbert, M. E., Colicos, M. A., Kandel, E. R., and Kuhl, D. (1993) Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation, Nature, 361, 453–457, doi:  https://doi.org/10.1038/361453a0.PubMedGoogle Scholar
  20. 20.
    Yepes, M., Sandkvist, M., Coleman, T. A., Moore, E., Wu, J. Y., Mitola, D., Bugge, T. H., and Lawrence, D. A. (2002) Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen-independent, J. Clin. Invest., 109, 1571–1578, doi:  https://doi.org/10.1172/JCI14308.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Benarroch, E. E. (2007) Tissue plasminogen activator, Neurology, 69, 799–802, doi:  https://doi.org/10.1212/01.wnl.0000269668.08747.78.CrossRefPubMedGoogle Scholar
  22. 22.
    Merino, P., Diaz, A., and Yepes, M. (2017) Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) promote neurorepair in the ischemic brain, Recept. Clin. Investig., 4, e1552.Google Scholar
  23. 23.
    Sashindranath, M., Sales, E., Daglas, M., Freeman, R., Samson, A. L., Cops, E. J., Beckham, S., Galle, A., McLean, C., Morganti-Kossmann, C., Rosenfeld, J. V., Madani, R., Vassalli, J. D., Su, E. J., Lawrence, D. A., and Medcalf, R. L. (2012) The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans, Brain, 135, 3251–3264, doi:  https://doi.org/10.1093/brain/aws178.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Czekay, R. P., Wilkins-Port, C. E., Higgins, S. P., Freytag, J., Overstreet, J. M., Klein, R. M., Higgins, C. E., Samarakoon, R., and Higgins, P. J. (2011) PAI-1: an integrator of cell signaling and migration, Int. J. Cell Biol., 2011, 1–9, doi:  https://doi.org/10.1155/2011/562481.CrossRefGoogle Scholar
  25. 25.
    Lee, T. W., Tsang, V. W. K., Loef, E. J., and Birch, N. P. (2017) Physiological and pathological functions of neuroserpin: regulation of cellular responses through multiple mechanisms, Semin. Cell Dev. Biol., 62, 152–159, doi:  https://doi.org/10.1016/j.semcdb.2016.09.007.CrossRefPubMedGoogle Scholar
  26. 26.
    Yepes, M., Sandkvist, M., Wong, M. K., Coleman, T. A., Smith, E., Cohan, S. L., and Lawrence, D. A. (2000) Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis, Blood, 96, 569–576.PubMedGoogle Scholar
  27. 27.
    Reumann, R., Vierk, R., Zhou, L., Gries, F., Kraus, V., Mienert, J., Romswinkel, E., Morellini, F., Ferrer, I., Nicolini, C., Fahnestock, M., Rune, G., Glatzel, M., and Galliciotti, G. (2017) The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior, Learn. Mem., 24, 650–659, doi:  https://doi.org/10.1101/lm.045864.117.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yepes, M., and Lawrence, D. A. (2004) Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system, Thromb. Haemost., 91, 457–464, doi:  https://doi.org/10.1160/TH03-12-0766.CrossRefPubMedGoogle Scholar
  29. 29.
    Ortolano, S., and Spuch, C. (2013) tPA in the central nervous system: relations between tPA and cell surface LRPs, Recent Pat. Endocr. Metab. Immune Drug Discov., 7, 65–76, doi:  https://doi.org/10.2174/1872214811307010065.CrossRefPubMedGoogle Scholar
  30. 30.
    Bi Oh, S., Suh, N., Kim, I., and Lee, J. Y. (2015) Impacts of aging and amyloid-β deposition on plasminogen activators and plasminogen activator inhibitor-1 in the Tg2576 mouse model of Alzheimer’s disease, Brain Res., 1597, 159–167, doi:  https://doi.org/10.1016/j.brainres.2014.11.042.CrossRefGoogle Scholar
  31. 31.
    Gerenu, G., Martisova, E., Ferrero, H., Carracedo, M., Rantamaki, T., Ramirez, M. J., and Gil-Bea, F. J. (2017) Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer’s neuropathology and cognitive deficits, Biochim. Biophys. Acta Mol. Basis Dis., 1863, 991–1001, doi:  https://doi.org/10.1016/j.bbadis.2017.01.023.CrossRefPubMedGoogle Scholar
  32. 32.
    Liu, R. M., van Groen, T., Katre, A., Cao, D., Kadisha, I., Ballinger, C., Wang, L., Carroll, S. L., and Li, L. (2011) Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer’s disease, Neurobiol. Aging, 32, 1079–1089, doi:  https://doi.org/10.1016/j.neurobiolaging.2009.06.003.CrossRefPubMedGoogle Scholar
  33. 33.
    Semina, E. V., Rubina, K. A., Stepanova, V. V., and Tkachuk, V. A. (2016) Urokinase receptor and its endogenous ligands in brain embryogenesis and formation of cognitive functions, Rus. J. Physiol., 102, 881–903.Google Scholar
  34. 34.
    Rubina, K. A., Semina, E. A., Balatskaya, M. N., Plekhanova, O. S., and Tkachuk, V. A. (2018) Mechanisms regulating directed nerve and vessel growth by components of fibrinolytic system and GPI-anchored navigation receptors, Rus. J. Physiol., 104, 1001–1026, doi:  https://doi.org/10.7868/S0869813918090010.Google Scholar
  35. 35.
    Barinka, C., Parry, G., Callahan, J., Shaw, D. E., Kuo, A., Bdeir, K., Cines, D. B., Mazar, A., and Lubkowski, J. (2006) Structural basis of interaction between urokinase-type plasminogen activator and its receptor, J. Mol. Biol., 363, 482–495, doi:  https://doi.org/10.1016/j.jmb.2006.08.063.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Sharonov, G. V., Balatskaya, M. N., and Tkachuk, V. A. (2016) Glycosylphosphatidylinositol-anchored proteins as regulators of cortical cytoskeleton, Biochemistry (Moscow), 81, 844–859, doi:  https://doi.org/10.1134/S0006297916060110.CrossRefGoogle Scholar
  37. 37.
    Lino, N., Fiore, L., Rapacioli, M., Teruel, L., Flores, V., Scicolone, G., and Sanchez, V. (2014) uPA-uPAR molecular complex is involved in cell signaling during neuronal migration and neuritogenesis, Dev. Dyn., 243, 676–689, doi:  https://doi.org/10.1002/dvdy.24114.CrossRefPubMedGoogle Scholar
  38. 38.
    Farias-Eisner, R., Vician, L., Silver, A., Reddy, S., Rabbani, S. A., and Herschman, H. R. (2000) The urokinase plasminogen activator receptor (UPAR) is preferentially induced by nerve growth factor in PC12 pheochromocytoma cells and is required for NGF-driven differentiation, J. Neurosci., 20, 230–239, doi:  https://doi.org/10.1523/JNEUROSCI.20-01-00230.2000.CrossRefPubMedGoogle Scholar
  39. 39.
    Eden, G., Archinti, M., Furlan, F., Murphy, R., and Degryse, B. (2011) The urokinase receptor interactome, Curr. Pharm. Des., 17, 1874–1889, doi:  https://doi.org/10.2174/138161211796718215.CrossRefPubMedGoogle Scholar
  40. 40.
    Jo, M., Thomas, K. S., O’Donnell, D. M., and Gonias, S. L. (2003) Epidermal growth factor receptor-dependent and -independent cell-signaling pathways originating from the urokinase receptor, J. Biol. Chem., 278, 1642–1646, doi:  https://doi.org/10.1074/jbc.M210877200.CrossRefPubMedGoogle Scholar
  41. 41.
    D’Alessio, S., and Blasi, F. (2009) The urokinase receptor as an entertainer of signal transduction, Front. Biosci., 14, 4575–4587, doi:  https://doi.org/10.2741/3550.CrossRefGoogle Scholar
  42. 42.
    Nykjar, A., Conese, M., Christensen, E. I., Olson, D., Cremona, O., Gliemann, J., and Blasi, F. (1997) Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes, EMBO J., 16, 2610–2620, doi:  https://doi.org/10.1093/emboj/16.10.2610.CrossRefGoogle Scholar
  43. 43.
    Seeds, N. W., Basham, M. E., and Haffke, S. P. (1999) Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene, Proc. Natl. Acad. Sci. USA, 96, 14118–14123, doi:  https://doi.org/10.1073/pnas.96.24.14118.CrossRefPubMedGoogle Scholar
  44. 44.
    Shin, S. M., Cho, K. S., Choi, M. S., Lee, S. H., Han, S.-H., Kang, Y. S., Kim, H. J., Cheong, J. H., Shin, C. Y., and Ko, K. H. (2010) Urokinase-type plasminogen activator induces BV-2 microglial cell migration through activation of matrix metalloproteinase-9, Neurochem. Res., 35, 976–985, doi:  https://doi.org/10.1007/s11064-010-0141-3.CrossRefPubMedGoogle Scholar
  45. 45.
    Lee, S. H., Ko, H. M., Kwon, K. J., Lee, J., Han, S. H., Han, D. W., Cheong, J. H., Ryu, J. H., and Shin, C. Y. (2014) tPA regulates neurite outgrowth by phosphorylation of LRP5/6 in neural progenitor cells, Mol. Neurobiol., 49, 199–215, doi:  https://doi.org/10.1007/s12035-013-8511-x.CrossRefPubMedGoogle Scholar
  46. 46.
    Powell, E. M., Campbell, D. B., Stanwood, G. D., Davis, C., Noebels, J. L., and Levitt, P. (2003) Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, dand behavioral dysfunction, J. Neurosci., 3, 622–631, doi:  https://doi.org/10.1523/JNEUROSCI.23-02-00622.2003.CrossRefGoogle Scholar
  47. 47.
    Eagleson, K. L., Bonnin, A., and Levitt, P. (2005) Region- and age-specific deficits in γ-aminobutyric acidergic neuron development in the telencephalon of the uPAR-/- mouse, J. Comp. Neurol., 489, 449–466, doi:  https://doi.org/10.1002/cne.20647.CrossRefPubMedGoogle Scholar
  48. 48.
    Lahtinen, L., Huusko, N., Myohanen, H., Lehtivarjo, A. K., Pellinen, R., Turunen, M. P., Yla-Herttuala, S., Pirinen, E., and Pitkanen, A. (2009) Expression of urokinase-type plasminogen activator receptor is increased during epileptogenesis in the rat hippocampus, Neuroscience, 163, 316–328, doi:  https://doi.org/10.1016/j.neuroscience.2009.06.019.CrossRefPubMedGoogle Scholar
  49. 49.
    Zarnadze, S., Bauerle, P., Santos-Torres, J., Bohm, C., Schmitz, D., Geiger, J. R., Dugladze, T., and Gloveli, T. (2016) Cell-specific synaptic plasticity induced by network oscillations, Elife, 5, e14912, doi:  https://doi.org/10.7554/eLife.14912.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Levitt, P. (2005) Disruption of interneuron development, Epilepsia, 46, 22–28, doi:  https://doi.org/10.1111/j.1528-1167.2005.00305.x.CrossRefPubMedGoogle Scholar
  51. 51.
    Powell, E. M., Mars, W. M., and Levitt, P. (2001) Hepatocyte growth factor/scatter factor is a motogen for interneurons migrating from the ventral to dorsal telencephalon, Neuron, 30, 79–89, doi:  https://doi.org/10.1016/S0896-6273(01)00264-1.CrossRefPubMedGoogle Scholar
  52. 52.
    Bolkvadze, T., Puhakka, N., and Pitkanen, A. (2016) Epileptogenesis after traumatic brain injury in Plaur-deficient mice, Epilepsy Behav., 60, 187–196, doi:  https://doi.org/10.1016/j.yebeh.2016.04.038.CrossRefPubMedGoogle Scholar
  53. 53.
    Ndode-Ekane, X. E., and Pitkanen, A. (2013) Urokinase-type plasminogen activator receptor modulates epilepto-genesis in mouse model of temporal lobe epilepsy, Mol. Neurobiol., 47, 914–937, doi:  https://doi.org/10.1007/s12035-012-8386-2.CrossRefPubMedGoogle Scholar
  54. 54.
    Bae, M. H., Bissonette, G. B., Mars, W. M., Michalopoulos, G. K., Achim, C. L., Depireux, D. A., and Powell, E. M. (2010) Hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility, Exp. Neurol., 221, 129–135, doi:  https://doi.org/10.1016/j.expneurol.2009.10.011.CrossRefPubMedGoogle Scholar
  55. 55.
    Bolkvadze, T., Rantala, J., Puhakka, N., Andrade, P., and Pitkanen, A. (2015) Epileptogenesis after traumatic brain injury in Plau-deficient mice, Epilepsy Behav., 51, 19–27, doi:  https://doi.org/10.1016/j.yebeh.2015.06.037.CrossRefPubMedGoogle Scholar
  56. 56.
    Rantala, J., Kemppainen, S., Ndode-Ekane, X. E., Lahtinen, L., Bolkvadze, T., Gurevicius, K., Tanila, H., and Pitkanen, A. (2015) Urokinase-type plasminogen activator deficiency has little effect on seizure susceptibility and acquired epilepsy phenotype but reduces spontaneous exploration in mice, Epilepsy Behav., 42, 117–128, doi:  https://doi.org/10.1016/j.yebeh.2014.11.001.CrossRefPubMedGoogle Scholar
  57. 57.
    Lahtinen, L., Ndode-Ekane, X. E., Barinka, F., Akamine, Y., Esmaeili, M. H., Rantala, J., and Pitkanen, A. (2010) Urokinase-type plasminogen activator regulates neurode-generation and neurogenesis but not vascular changes in the mouse hippocampus after status epilepticus, Neurobiol. Dis., 37, 692–703, doi:  https://doi.org/10.1016/j.nbd.2009.12.008.CrossRefPubMedGoogle Scholar
  58. 58.
    Pawlak, R., Rao, B. S., Melchor, J. P., Chattarji, S., McEwen, B., and Strickland, S. (2005) Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus, Proc. Natl. Acad. Sci. USA, 102, 18201–18206, doi:  https://doi.org/10.1073/pnas.0509232102.CrossRefPubMedGoogle Scholar
  59. 59.
    Vezzani, A. (2005) Tissue plasminogen activator, neuroserpin, and seizures, Epilepsy Curr., 5, 130–132, doi:  https://doi.org/10.1111/J.1535-7511.2005.00041.X.CrossRefGoogle Scholar
  60. 60.
    Campbell, D. B., Li, C., Sutcliffe, J. S., Persico, A. M., and Levitt, P. (2008) Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder, Autism Res., 1, 159–168, doi:  https://doi.org/10.1002/aur.27.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zandifar, A., Soleimani, S., Iraji, N., Haghdoost, F., Tajaddini, M., and Javanmard, S. H. (2014) Association between promoter region of the uPAR (rs344781) gene polymorphism in genetic susceptibility to migraine without aura in three Iranian hospitals, Clin. Neurol. Neurosurg., 120, 45–48, doi:  https://doi.org/10.1016/jclineuro.2014.02.003.CrossRefPubMedGoogle Scholar
  62. 62.
    Roll, P., Rudolf, G., Pereira, S., Royer, B., Scheffer, I. E., Massacrier, A., Valenti, M. P., Roeckel-Trevisiol, N., Jamali, S., Beclin, C., Seegmuller, C., Metz-Lutz, M. N., Lemainque, A., Delepine, M., Caloustian, C., Martin, A. de Saint, Bruneau, N., Depetris, D., Mattei, M. G., Flori, E., Robaglia-Schlupp, A., Levy, N., Neubauer, B. A., Ravid, R., Marescaux, C., Berkovic, S. F., Hirsch, E., Lathrop, M., Cau, P., and Szepetowski, P. (2006) SRPX2 mutations in disorders of language cortex and cognition, Hum. Mol. Genet., 15, 1195–1207, doi:  https://doi.org/10.1093/hmg/ddl035.CrossRefPubMedGoogle Scholar
  63. 63.
    Samson, A. L., and Medcalf, R. L. (2006) Tissue-type plasminogen activator: a multifaceted modulator of neuro-transmission and synaptic plasticity, Neuron, 50, 673–678, doi:  https://doi.org/10.1016/j.neuron.2006.04.013.CrossRefPubMedGoogle Scholar
  64. 64.
    Seeds, N. W., Basham, M. E., and Ferguson, J. E. (2003) Absence of tissue plasminogen activator gene or activity impairs mouse cerebellar motor learning, J. Neurosci., 23, 7368–7375, doi:  https://doi.org/10.1523/JNEUROSCI.23-19-07368.2003.CrossRefPubMedGoogle Scholar
  65. 65.
    Madani, R., Hulo, S., Toni, N., Madani, H., Steimer, T., Muller, D., and Vassalli, J. D. (1999) Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice, EMBO J., 18, 3007–3012, doi:  https://doi.org/10.1093/emboj/18.11.3007.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bennur, S., Shankaranarayana Rao, B. S., Pawlak, R., Strickland, S., McEwen, B. S., and Chattarji, S. (2007) Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator, Neuroscience, 144, 8–16, doi:  https://doi.org/10.1016/j.neuroscience.2006.08.075.CrossRefPubMedGoogle Scholar
  67. 67.
    Tsirka, S. E., Gualandris, A., Amaral, D. G., and Strickland, S. (1995) Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator, Nature, 377, 340–344, doi:  https://doi.org/10.1038/377340a0.CrossRefPubMedGoogle Scholar
  68. 68.
    Beschorner, R., Schluesener, H. J., Nguyen, T. D., Magdolen, V., Luther, T., Pedal, I., Mattern, R., Meyermann, R., and Schwab, J. M. (2000) Lesion-associated accumulation of uPAR/CD87-expressing infiltrating granulocytes, activated microglial cells/macrophages and upregulation by endothelial cells following TBI and FCI in humans, Neuropathol. Appl. Neurobiol., 26, 522–527, doi:  https://doi.org/10.1046/j.0305-1846.2000.287.x.CrossRefPubMedGoogle Scholar
  69. 69.
    Walker, D. G., Lue, L. F., and Beach, T. G. (2002) Increased expression of the urokinase plasminogen-activator receptor in amyloid beta peptide-treated human brain microglia and in AD brains, Brain Res., 926, 69–79, doi:  https://doi.org/10.1016/S0006-8993(01)03298-X.CrossRefPubMedGoogle Scholar
  70. 70.
    Washington, R. A., Becher, B., Balabanov, R., Antel, J., and Dore-Duffy, P. (1996) Expression of the activation marker urokinase plasminogen-activator receptor in cultured human central nervous system microglia, J. Neurosci. Res., 45, 392–399, doi:  https://doi.org/10.1002/(SICI)1097-4547(19960815)45:4<392::AID-JNR8>3.0.CO;2-4.CrossRefPubMedGoogle Scholar
  71. 71.
    Cunningham, O., Campion, S., Perry, V. H., Murray, C., Sidenius, N., Docagne, F., and Cunningham, C. (2009) Microglia and the urokinase plasminogen activator receptor/uPA system in innate brain inflammation, Glia, 57, 1802–1814, doi:  https://doi.org/10.1002/glia.20892.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Choi, J., and Koh, S. (2008) Role of brain inflammation in epileptogenesis, Yonsei Med. J., 49, 1–18, doi:  https://doi.org/10.3349/ymj.2008.49.1.1.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Nagai, N., Okada, K., Kawao, N., Ishida, C., Ueshima, S., Collen, D., and Matsuo, O. (2008) Urokinase-type plasminogen activator receptor (uPAR) augments brain damage in a murine model of ischemic stroke, Neurosci. Lett., 432, 46–49, doi:  https://doi.org/10.1016/j.neulet.2007.12.004.CrossRefPubMedGoogle Scholar
  74. 74.
    Gur-Wahnon, D., Mizrachi, T., Maaravi-Pinto, F. Y., Lourbopoulos, A., Grigoriadis, N., Higazi, A. A., and Brenner, T. (2013) The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention, J. Neuroinflammation, 10, 891, doi:  https://doi.org/10.1186/1742-2094-10-124.CrossRefGoogle Scholar
  75. 75.
    Deininger, M. H., Trautmann, K., Magdolen, V., Luther, T., Schluesener, H. J., and Meyermann, R. (2002) Cortical neurons of Creutzfeldt-Jakob disease patients express the urokinase-type plasminogen activator receptor, Neurosci. Lett., 324, 80–82, doi:  https://doi.org/10.1016/S0304-3940(02)00168-4.CrossRefPubMedGoogle Scholar
  76. 76.
    Iyer, A. M., Zurolo, E., Boer, K., Baayen, J. C., Giangaspero, F., Arcella, A., Di Gennaro, G. C., Esposito, V., Spliet, W. G., van Rijen, P. C., Troost, D., Gorter, J. A., and Aronica, E. (2010) Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies, Neuroscience, 167, 929–945, doi:  https://doi.org/10.1016/j.neuroscience.2010.02.047.CrossRefPubMedGoogle Scholar
  77. 77.
    Liu, B., Zhang, B., Wang, T., Liang, Q. C., Jing, X. R., Zheng, J., Wang, C., Meng, Q., Wang, L., Wang, W., Guo, H., You, Y., Zhang, H., and Gao, G. D. (2010) Increased expression of urokinase-type plasminogen activator receptor in the frontal cortex of patients with intractable frontal lobe epilepsy, J. Neurosci. Res., 88, 2747–2754, doi:  https://doi.org/10.1002/jnr.22419.PubMedGoogle Scholar
  78. 78.
    Quirico-Santos, T., Nascimento Mello, A., Casimiro Gomes, A., de Carvalho, L. P., de Souza, J. M., and Alves-Leon, S. (2013) Increased metalloprotease activity in the epileptogenic lesion - lobectomy reduces metalloprotease activity and urokinase-type uPAR circulating levels, Brain Res., 1538, 172–181, doi:  https://doi.org/10.1016/j.brainres.2013.09.044.CrossRefPubMedGoogle Scholar
  79. 79.
    Lahtinen, L., Lukasiuk, K., and Pitkanen, A. (2006) Increased expression and activity of urokinase-type plasminogen activator during epileptogenesis, Eur. J. Neurosci., 24, 1935–1945, doi:  https://doi.org/10.1111/j.1460-9568.2006.05062.x.CrossRefPubMedGoogle Scholar
  80. 80.
    Gorter, J. A., van Vliet, E. A., Aronica, E., Breit, T., Rauwerda, H., Lopes da Silva, F. H., and Wadman, W. J. (2006) Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy, J. Neurosci., 26, 11083–11110, doi:  https://doi.org/10.1523/JNEUROSCI.2766-06.2006.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Gorter, J. A., Van Vliet, E. A., Rauwerda, H., Breit, T., Stad, R., van Schaik, L., Vreugdenhil, E., Redeker, S., Hendriksen, E., Aronica, E., da Silva, F. H. L., and Wadman, W. J. (2007) Dynamic changes of proteases and protease inhibitors revealed by microarray analysis in CA3 and entorhinal cortex during epileptogenesis in the rat, Epilepsia, 48, 53–64, doi:  https://doi.org/10.1111/j.1528-1167.2007.01290.x.CrossRefPubMedGoogle Scholar
  82. 82.
    Carroll, P. M., Tsirka, S. E., Richards, W. G., Frohman, M. A., and Strickland, S. (1994) The mouse tissue plasminogen activator gene 5′ flanking region directs appropriate expression in development and a seizure-enhanced response in the CNS, Development, 120, 3173–3183.PubMedGoogle Scholar
  83. 83.
    Salles, F. J., and Strickland, S. (2002) Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus, J. Neurosci., 22, 2125–2134, doi:  https://doi.org/10.1523/JNEUROSCI.22-06-02125.2002.CrossRefPubMedGoogle Scholar
  84. 84.
    Haile, W. B., Wu, J., Echeverry, R., Wu, F., An, J., and Yepes, M. (2012) Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-α, J. Cereb. Blood Flow Metab., 32, 57–69, doi:  https://doi.org/10.1038/jcbfm.2011.106.CrossRefPubMedGoogle Scholar
  85. 85.
    Grummisch, J. A., Jadavji, N. M., and Smith, P. D. (2016) tPA promotes cortical neuron survival via mTOR-dependent mechanisms, Mol. Cell. Neurosci., 74, 25–33, doi:  https://doi.org/10.1016/j.mcn.2016.03.005.CrossRefPubMedGoogle Scholar
  86. 86.
    Lukasiuk, K., Kontula, L., and Pitkanen, A. (2003) cDNA profiling of epileptogenesis in the rat brain, Eur. J. Neurosci., 17, 271–279, doi:  https://doi.org/10.1046/j.1460-9568.2003.02461.x.CrossRefPubMedGoogle Scholar
  87. 87.
    Masos, T., and Miskin, R. (1997) mRNAs encoding urokinase-type plasminogen activator and plasminogen activator inhibitor-1 are elevated in the mouse brain following kainate-mediated excitation, Brain Res. Mol. Brain Res., 47, 157–169, doi:  https://doi.org/10.1016/S0169-328X(97)00040-5.CrossRefPubMedGoogle Scholar
  88. 88.
    Siconolfi, L. B., and Seeds, N. W. (2001) Induction of the plasminogen activator system accompanies peripheral nerve regeneration after sciatic nerve crush, J. Neurosci., 21, 4336–4347, doi:  https://doi.org/10.1523/JNEUROSCI.21-12-04336.2001.CrossRefPubMedGoogle Scholar
  89. 89.
    Diaz, A., Merino, P., Manrique, L. G., Ospina, J. P., Cheng, L., Wu, F., Jeanneret, V., and Yepes, M. (2017) A cross talk between neuronal urokinase-type plasminogen activator (uPA) and astrocytic uPA receptor (uPAR) promotes astrocytic activation and synaptic recovery in the ischemic brain, J. Neurosci., 37, 10310–10322, doi:  https://doi.org/10.1523/JNEUROSCI.1630-17.2017.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Thornton, P., Pinteaux, E., Allan, S. M., and Rothwell, N. J. (2008) Matrix metalloproteinase-9 and urokinase plasminogen activator mediate interleukin-1-induced neurotoxicity, Mol. Cell. Neurosci., 37, 135–142, doi:  https://doi.org/10.1016/j.mcn.2007.09.002.CrossRefPubMedGoogle Scholar
  91. 91.
    Eisener-Dorman, A. F., Lawrence, D. A., and Bolivar, V. J. (2009) Cautionary insights on knockout mouse studies: the gene or not the gene? Brain. Behav. Immun., 23, 318–324, doi:  https://doi.org/10.1016/j.bbi.2008.09.001.CrossRefPubMedGoogle Scholar
  92. 92.
    Soeda, S., Koyanagi, S., Kuramoto, Y., Kimura, M., Oda, M., Kozako, T., Hayashida, S., and Shimeno, H. (2008) Anti-apoptotic roles of plasminogen activator inhibitor-1 as a neurotrophic factor in the central nervous system, Thromb. Haemost., 100, 1014–1020, doi:  https://doi.org/10.1160/TH08-04-0259.CrossRefPubMedGoogle Scholar
  93. 93.
    Rysenkova, K. D., Semina, E. V., Karagyaur, M. N., Shmakova, A. A., Dyikanov, D. T., Vasiluev, P. A., Rubtsov, Y. P., Rubina, K. A., and Tkachuk, V. A. (2018) CRISPR/Cas9 nickase mediated targeting of urokinase receptor gene inhibits neuroblastoma cell proliferation, Oncotarget, 9, 29414–29430, doi:  https://doi.org/10.18632/oncotarget.25647.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Shu, Y. H., Lu, X. M., Wei, J. X., Xiao, L., and Wang, Y. T. (2015) Update on the role of p75NTR in neurological disorders: a novel therapeutic target, Biomed. Pharmacother., 76, 17–23, doi:  https://doi.org/10.1016/j.biopha.2015.10.010.CrossRefPubMedGoogle Scholar
  95. 95.
    Blochl, A., and Blochl, R. (2007) A cell-biological model of p75NTR signaling, J. Neurochem., 102, 289–305, doi:  https://doi.org/10.1111/j.1471-4159.2007.04496.x.CrossRefPubMedGoogle Scholar
  96. 96.
    Friedman, W. J. (2010) Proneurotrophins, seizures, and neuronal apoptosis, Neuroscientist, 16, 244–252, doi:  https://doi.org/10.1177/1073858409349903.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Soren Leonard, A., Puranam, R. S., Helgager, J., Liu, G., and McNamara, J. O. (2012) Conditional deletion of TrkC does not modify limbic epileptogenesis, Epilepsy Res., 102, 126–130, doi:  https://doi.org/10.1016/j.eplepsyres.2012.07.019.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Volosin, M., Trotter, C., Cragnolini, A., Kenchappa, R. S., Light, M., Hempstead, B. L., Carter, B. D., and Friedman, W. J. (2008) Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures, J. Neurosci., 28, 9870–9879, doi:  https://doi.org/10.1523/JNEUROSCI.2841-08.2008.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Unsain, N., Nunez, N., Anastasia, A., and Masco, D. H. (2008) Status epilepticus induces a TrkB to p75 neurotrophin receptor switch and increases brain-derived neurotrophic factor interaction with p75 neurotrophin receptor: an initial event in neuronal injury induction, Neuroscience, 154, 978–993, doi:  https://doi.org/10.1016/j.neuroscience.2008.04.038.CrossRefPubMedGoogle Scholar
  100. 100.
    Riffault, B., Kourdougli, N., Dumon, C., Ferrand, N., Buhler, E., Schaller, F., Chambon, C., Rivera, C., Gaiarsa, J. L., and Porcher, C. (2018) Pro-brain-derived neurotrophic factor (proBDNF)-mediated p75NTR activation promotes depolarizing actions of GABA and increases susceptibility to epileptic seizures, Cereb. Cortex, 28, 510–527, doi:  https://doi.org/10.1093/cercor/bhw385.CrossRefPubMedGoogle Scholar
  101. 101.
    Porcher, C., Medina, I., and Gaiarsa, J. L. (2018) Mechanism of BDNF modulation in GABAergic synaptic transmission in healthy and disease brains, Front. Cell. Neurosci., 12, 273, doi:  https://doi.org/10.3389/fncel.2018.00273.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Holm, M. M., Nieto-Gonzalez, J. L., Vardya, I., Vaegter, C. B., Nykjaer, A., and Jensen, K. (2009) Mature BDNF, but not proBDNF, reduces excitability of fast-spiking interneurons in mouse dentate gyrus, J. Neurosci., 29, 12412–12418, doi:  https://doi.org/10.1523/JNEUROSCI.2978-09.2009.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Salazar, I. L., Caldeira, M. V., Curcio, M., and Duarte, C. B. (2016) The role of proteases in hippocampal synaptic plasticity: putting together small pieces of a complex puzzle, Neurochem. Res., 41, 156–182, doi:  https://doi.org/10.1007/s11064-015-1752-5.CrossRefPubMedGoogle Scholar
  104. 104.
    Nagappan, G., Zaitsev, E., Senatorov, V. V., Yang, J., Hempstead, B. L., and Lu, B. (2009) Control of extracellular cleavage of ProBDNF by high frequency neuronal activity, Proc. Natl. Acad. Sci. USA, 106, 1267–1272, doi:  https://doi.org/10.1073/pnas.0807322106.CrossRefPubMedGoogle Scholar
  105. 105.
    Thomas, A. X., Cruz Del Angel, Y., Gonzalez, M. I., Carrel, A. J., Carlsen, J., Lam, P. M., Hempstead, B. L., Russek, S. J., and Brooks-Kayal, A. R. (2016) Rapid increases in proBDNF after pilocarpine-induced status epilepticus in mice are associated with reduced proBDNF cleavage machinery, eNeuro, 3 (1), pii: ENEURO.0020-15.2016, doi:  https://doi.org/10.1523/ENEURO.0020-15.2016.
  106. 106.
    Su, F., Kozak, K. R., Herschman, H., Reddy, S. T., and Farias-Eisner, R. (2007) Characterization of the rat urokinase plasminogen activator receptor promoter in PC12 cells, J. Neurosci. Res., 85, 1952–1958, doi:  https://doi.org/10.1002/jnr.21296.CrossRefPubMedGoogle Scholar
  107. 107.
    Rohe, M., Synowitz, M., Glass, R., Paul, S. M., Nykjaer, A., and Willnow, T. E. (2009) Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression, J. Neurosci., 29, 15472–15478, doi:  https://doi.org/10.1523/JNEUROSCI.3960-09.2009.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Gliemann, J., Hermey, G., Nykjaer, A., Petersen, C. M., Jacobsen, C., and Andreasen, P. A. (2004) The mosaic receptor sorLA/LR11 binds components of the plasminogen-activating system and platelet-derived growth factor-BB similarly to LRP1 (low-density lipoprotein receptor-related protein), but mediates slow internalization of bound ligand, Biochem. J., 381, 203–212, doi:  https://doi.org/10.1042/BJ20040149.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • A. A. Shmakova
    • 1
  • K. A. Rubina
    • 1
  • K. V. Anokhin
    • 2
  • V. A. Tkachuk
    • 1
    • 3
  • E. V. Semina
    • 1
    • 3
    Email author
  1. 1.Lomonosov Moscow State University, Faculty of Medicine, Laboratory of Gene and Cell TechnologiesMoscowRussia
  2. 2.Lomonosov Moscow State University, Institute for Advanced Brain StudiesMoscowRussia
  3. 3.National Cardiology Research Center, Ministry of Health of the Russian Federation, Laboratory of Molecular EndocrinologyMoscowRussia

Personalised recommendations