Journal of Molecular Neuroscience

, Volume 68, Issue 1, pp 91–98 | Cite as

Smad Anchor for Receptor Activation and Phospho-Smad3 Were Upregulated in Patients with Temporal Lobe Epilepsy

  • Wenbo Zhang
  • Yingshi Du
  • Yan Zou
  • Jing Luo
  • Yang Lü
  • Weihua YuEmail author


Smad anchor for receptor activation (SARA) is an important regulator of transforming growth factor β (TGF-β) signaling by recruiting Smad2/3 to TGF-β receptors. We recently demonstrated that the expressions of SARA and level of downstream phospho-Smad3 (p-Smad3) were upregulated in the brain in the epileptic rat model, but were never examined in patients with temporal lobe epilepsy (TLE). In this study, we examined the expressions of SARA and level of p-Smad3 in brain tissues of TLE patients using immunohistochemistry and western blot to demonstrate that SARA activation in neurons is sufficient to facilitate TGF- β pathway in patients to regulate epilepsy. We found that the expressions of SARA and level of p-Smad3 were significantly upregulated in neurons of the temporal cortex of TLE patients compared to controls. Moreover, SARA and p-Smad3 were strongly stained in the cytoplasm in the temporal cortex of TLE patients. Our results indicate that upregulation of SARA and p-Smad3 in cortex neurons might be involved in the development of intractable temporal lobe epilepsy.


SARA Seizure Smad3 TGF-β Temporal lobe epilepsy Patient 



We sincerely appreciate all of the patients and their families for their participation in this study.


This study was supported by grants from the National Natural Science Foundation of China (81671286 and 81871019), and Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJ1702011).

Compliance with Ethical Standards

All procedures were carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans, and were approved by the National Institutes of Health and the Committee on Human Research at the Chongqing Medical University. The formal consents were obtained from the patients or their legal next of kin for the use of any data and tissues for research studies.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12031_2019_1285_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1309 kb)


  1. Bui AD, Nguyen TM, Limouse C, Kim HK, Szabo GG, Felong S, Maroso M, Soltesz I (2018) Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory. Science 359(6377):787–790CrossRefGoogle Scholar
  2. de Vries EE, van den Munckhof B, Braun KP, van Royen-Kerkhof A, de Jager W, Jansen FE (2016) Inflammatory mediators in human epilepsy: a systematic review and meta-analysis. Neurosci Biobehav Rev 63:177–190CrossRefGoogle Scholar
  3. Dohgu S, Takata F, Yamauchi A, Nakagawa S, Egawa T, Naito M, Tsuruo T, Sawada Y, Niwa M, Kataoka Y (2005) Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production. Brain Res 1038:208–215CrossRefGoogle Scholar
  4. Du Y, Zou Y, Yu W, Shi R, Zhang M, Yang W, Duan J, Deng Y, Wang X, Lü Y (2013) Expression pattern of sorting nexin 25 in temporal lobe epilepsy: a study on patients and pilocarpine-induced rats. Brain Res 1509:79–85CrossRefGoogle Scholar
  5. Heldin CH, Moustakas A (2016) Signaling receptors for TGF-β family members. Cold Spring Harb Perspect Biol 8:a022053. CrossRefGoogle Scholar
  6. Hill CS (2016) Transcriptional control by the SMADs. Cold Spring Harb Perspect Biol 8:a022079. CrossRefGoogle Scholar
  7. Hu HH, Chen DQ, Wang NY, Feng YL, Cao G, Vaziri ND, Zhao YY (2018) New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact 292:76–83CrossRefGoogle Scholar
  8. Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A (2007) TGF-β receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130:535–547CrossRefGoogle Scholar
  9. Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172(7):973–981CrossRefGoogle Scholar
  10. Librizzi L, Regondi MC, Pastori C, Frigerio S, Frassoni C, de Curtis M (2007) Expression of adhesion factors induced by epileptiform activity in the endothelium of the isolated guinea pig brain in vitro. Epilepsia 48:743–751CrossRefGoogle Scholar
  11. Lu Y, Xue T, Yuan J, Li Y, Wu Y, Xi Z, Xiao Z, Chen Y, Wang X (2009) Increased expression of TGFbeta type I receptor in brain tissues of patients with temporal lobe epilepsy. Clin Sci (Lond) 117:17–22CrossRefGoogle Scholar
  12. Marchi N, Granata T, Janigro D (2014) Inflammatory pathways of seizure disorders. Trends Neurosci 37(2):55–65CrossRefGoogle Scholar
  13. Mishra L, Marshall B (2006) Adaptor proteins and ubiquinators in TGF-beta signaling. Cytokine Growth Factor Rev 17:75–87CrossRefGoogle Scholar
  14. Morikawa M, Derynck R, Miyazono K (2016) TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol 8:a021873CrossRefGoogle Scholar
  15. Paul D, Dixit A, Srivastava A, Tripathi M, Prakash D, Sarkar C, Ramanujam B, Banerjee J, Chandra PS (2018) Altered transforming growth factor beta/SMAD3 signalling in patients with hippocampal sclerosis. Epilepsy Res 146:144–150CrossRefGoogle Scholar
  16. Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB (1981) New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A 78:5339–5343CrossRefGoogle Scholar
  17. Ronaldson PT, Demarco KM, Sanchez-Covarrubias L, Solinsky CM, Davis TP (2009) Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain. J Cereb Blood Flow Metab 29(6):1084–1098CrossRefGoogle Scholar
  18. Runyan CE, Hayashida T, Hubchak S, Curley JF, Schnaper HW (2009) Role of SARA(SMAD anchor for receptor activation) in maintenance of epithelial cell phenotype. J Biol Chem 284(37):25181–25189CrossRefGoogle Scholar
  19. Sirin NG, Yilmaz E, Bebek N, Baykan B, Gokyigit A, Gurses C (2018) Unusual ictal propagation patterns suggesting poor prognosis after temporal lobe epilepsy surgery: switch of lateralization and bilateral asynchrony. Epilepsy Behav 36:31–36CrossRefGoogle Scholar
  20. Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24CrossRefGoogle Scholar
  21. Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370:341–347CrossRefGoogle Scholar
  22. Yang Y, Tian X, Xu D, Zheng F, Lu X, Zhang Y, Ma Y, Li Y, Xu X, Zhu B, Wang X (2018) GPR40 modulates epileptic seizure and NMDA receptor function. Sci Adv 4:eaau2357. CrossRefGoogle Scholar
  23. Yu W, Du Y, Zou Y, Wang X, Stephani U, Lü Y (2017) Smad anchor for receptor activation contributes to seizures in temporal lobe epilepsy. Synapse 71(3):e21957CrossRefGoogle Scholar
  24. Zhang YE (2017) Non-Smad signaling pathways of TGF-β family. Cold Spring Harb Perspect Biol 9:a022129CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Neuroscience, Department of Human AnatomyChongqing Medical UniversityChongqingChina
  2. 2.Department of GeriatricsThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  3. 3.Department of NeurologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

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