Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries

Nature Medicine volume 15, pages 1399–1406 (2009)Cite this article

Abstract

Excitotoxic neuronal damage caused by overactivation of N-methyl-D-aspartate glutamate receptors (NMDARs) is thought to be a principal cause of neuronal loss after stroke and brain trauma. Here we report that activation of sterol regulatory element binding protein-1 (SREBP-1) transcription factor in affected neurons is an essential step in NMDAR-mediated excitotoxic neuronal death in both in vitro and in vivo models of stroke. The NMDAR-mediated activation of SREBP-1 is a result of increased insulin-induced gene-1 (Insig-1) degradation, which can be inhibited with an Insig-1–derived interference peptide (Indip) that we have developed. Using a focal ischemia model of stroke, we show that systemic administration of Indip not only prevents SREBP-1 activation but also substantially reduces neuronal damage and improves behavioral outcome. Our study suggests that agents that reduce SREBP-1 activation such as Indip may represent a new class of neuroprotective therapeutics against stroke.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SREBP-1 is activated in a time- and calcium-sensitive calpain-dependent manner in response to NMDA insult in cortical neuronal cultures.
Figure 2: Nuclear translocation of nt-SREBP-1 is induced by NMDA insult and is associated with neuronal apoptosis.
Figure 3: Reduced mature nt-SREBP-1 protects against NMDA-induced excitotoxicity.
Figure 4: Indip reduces NMDA-dependent SREBP-1 activation by decreasing Insig-1 ubiquitination and degradation.
Figure 5: Indip protects against NMDA-induced excitotoxicity and OGD-induced neuronal death in neuronal cultures.
Figure 6: Indip blocks MCAo-induced SREBP-1 activation and protects against ischemia-induced neuronal damage and behavioral deficits.

Similar content being viewed by others

References

  1. Choi, D.W. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 11, 465–469 (1988).

    Article  CAS  Google Scholar 

  2. Lipton, S.A. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat. Rev. Drug Discov. 5, 160–170 (2006).

    Article  CAS  Google Scholar 

  3. Ikonomidou, C. & Turski, L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol. 1, 383–386 (2002).

    Article  CAS  Google Scholar 

  4. Kemp, J.A. & McKernan, R.M. NMDA receptor pathways as drug targets. Nat. Neurosci. 5 (Suppl), 1039–1042 (2002).

    Article  CAS  Google Scholar 

  5. Lee, J.M., Zipfel, G.J. & Choi, D.W. The changing landscape of ischaemic brain injury mechanisms. Nature 399, A7–A14 (1999).

    Article  CAS  Google Scholar 

  6. Aarts, M. et al. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 298, 846–850 (2002).

    Article  CAS  Google Scholar 

  7. Camandola, S. & Mattson, M.P. NF-κB as a therapeutic target in neurodegenerative diseases. Expert Opin. Ther. Targets 11, 123–132 (2007).

    Article  CAS  Google Scholar 

  8. Hardingham, G.E., Arnold, F.J. & Bading, H. Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat. Neurosci. 4, 261–267 (2001).

    Article  CAS  Google Scholar 

  9. Hetman, M. & Kharebava, G. Survival signaling pathways activated by NMDA receptors. Curr. Top. Med. Chem. 6, 787–799 (2006).

    Article  CAS  Google Scholar 

  10. Rao, V.R. & Finkbeiner, S. NMDA and AMPA receptors: old channels, new tricks. Trends Neurosci. 30, 284–291 (2007).

    Article  CAS  Google Scholar 

  11. West, A.E., Griffith, E.C. & Greenberg, M.E. Regulation of transcription factors by neuronal activity. Nat. Rev. Neurosci. 3, 921–931 (2002).

    Article  CAS  Google Scholar 

  12. Zhang, S.J. et al. Decoding NMDA receptor signaling: identification of genomic programs specifying neuronal survival and death. Neuron 53, 549–562 (2007).

    Article  CAS  Google Scholar 

  13. Zou, J. & Crews, F. CREB and NF-κB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death. Cell. Mol. Neurobiol. 26, 385–405 (2006).

    Article  CAS  Google Scholar 

  14. Espenshade, P.J. & Hughes, A.L. Regulation of sterol synthesis in eukaryotes. Annu. Rev. Genet. 41, 401–427 (2007).

    Article  CAS  Google Scholar 

  15. Goldstein, J.L., DeBose-Boyd, R.A. & Brown, M.S. Protein sensors for membrane sterols. Cell 124, 35–46 (2006).

    Article  CAS  Google Scholar 

  16. Adibhatla, R.M., Hatcher, J.F. & Dempsey, R.J. Lipids and lipidomics in brain injury and diseases. AAPS J. 8, E314–E321 (2006).

    Article  Google Scholar 

  17. Siesjö, B.K. & Katsura, K. Ischemic brain damage: focus on lipids and lipid mediators. Adv. Exp. Med. Biol. 318, 41–56 (1992).

    Article  Google Scholar 

  18. Sandberg, M.B. et al. Glucose-induced lipogenesis in pancreatic beta cells is dependent on SREBP-1. Mol. Cell. Endocrinol. 240, 94–106 (2005).

    Article  CAS  Google Scholar 

  19. Takahashi, A. et al. Transgenic mice overexpressing nuclear SREBP-1c in pancreatic beta cells. Diabetes 54, 492–499 (2005).

    Article  CAS  Google Scholar 

  20. Wang, H. et al. The transcription factor SREBP-1c is instrumental in the development of betacell dysfunction. J. Biol. Chem. 278, 16622–16629 (2003).

    Article  CAS  Google Scholar 

  21. Wang, H., Kouri, G. & Wollheim, C.B. ER stress and SREBP-1 activation are implicated in beta cell glucolipotoxicity. J. Cell Sci. 118, 3905–3915 (2005).

    Article  CAS  Google Scholar 

  22. Yamashita, T. et al. Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a beta cell lipotoxicity model overexpressing sterol regulatory element–binding protein-1c. Endocrinology 145, 3566–3577 (2004).

    Article  CAS  Google Scholar 

  23. Chang, Y.C., Bien, C.M., Lee, H., Espenshade, P.J. & Kwon-Chung, K.J. Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans. Mol. Microbiol. 64, 614–629 (2007).

    Article  CAS  Google Scholar 

  24. Todd, B.L., Stewart, E.V., Burg, J.S., Hughes, A.L. & Espenshade, P.J. Sterol regulatory element binding protein is a principal regulator of anaerobic gene expression in fission yeast. Mol. Cell. Biol. 26, 2817–2831 (2006).

    Article  CAS  Google Scholar 

  25. Taghibiglou, C. et al. Essential role of SBP-1 activation in oxygen deprivation induced lipid accumulation and increase in body width/length ratio in Caenorhabditis elegans. FEBS Lett. 583, 831–834 (2009).

    Article  CAS  Google Scholar 

  26. Hardingham, G.E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414 (2002).

    Article  CAS  Google Scholar 

  27. Liu, Y. et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J. Neurosci. 27, 2846–2857 (2007).

    Article  CAS  Google Scholar 

  28. Zhou, M. & Baudry, M. Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors. J. Neurosci. 26, 2956–2963 (2006).

    Article  CAS  Google Scholar 

  29. Liu, L. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021–1024 (2004).

    Article  CAS  Google Scholar 

  30. Tigaret, C.M. et al. Subunit dependencies of N-methyl-d-aspartate (NMDA) receptor–induced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. Mol. Pharmacol. 69, 1251–1259 (2006).

    Article  CAS  Google Scholar 

  31. Mutel, V. et al. In vitro binding properties in rat brain of [3H]Ro 25–6981, a potent and selective antagonist of NMDA receptors containing NR2B subunits. J. Neurochem. 70, 2147–2155 (1998).

    Article  CAS  Google Scholar 

  32. Mattson, M.P. Calcium and neurodegeneration. Aging Cell 6, 337–350 (2007).

    Article  CAS  Google Scholar 

  33. Wang, X. et al. Cleavage of sterol regulatory element binding proteins (SREBPs) by CPP32 during apoptosis. EMBO J. 15, 1012–1020 (1996).

    Article  CAS  Google Scholar 

  34. Horton, J.D. et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl. Acad. Sci. USA 100, 12027–12032 (2003).

    Article  CAS  Google Scholar 

  35. Horton, J.D. et al. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element–binding protein-2. J. Clin. Invest. 101, 2331–2339 (1998).

    Article  CAS  Google Scholar 

  36. Nohturfft, A., Brown, M.S. & Goldstein, J.L. Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain. J. Biol. Chem. 273, 17243–17250 (1998).

    Article  CAS  Google Scholar 

  37. Sun, L.P., Li, L., Goldstein, J.L. & Brown, M.S. Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. J. Biol. Chem. 280, 26483–26490 (2005).

    Article  CAS  Google Scholar 

  38. Yang, T. et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110, 489–500 (2002).

    Article  CAS  Google Scholar 

  39. Gong, Y. et al. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab. 3, 15–24 (2006).

    Article  CAS  Google Scholar 

  40. Lee, J.N., Gong, Y., Zhang, X. & Ye, J. Proteasomal degradation of ubiquitinated Insig proteins is determined by serine residues flanking ubiquitinated lysines. Proc. Natl. Acad. Sci. USA 103, 4958–4963 (2006).

    Article  CAS  Google Scholar 

  41. Lee, J.N., Song, B., DeBose-Boyd, R.A. & Ye, J. Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78. J. Biol. Chem. 281, 39308–39315 (2006).

    Article  CAS  Google Scholar 

  42. Lee, J.N. & Ye, J. Proteolytic activation of sterol regulatory element–binding protein induced by cellular stress through depletion of Insig-1. J. Biol. Chem. 279, 45257–45265 (2004).

    Article  CAS  Google Scholar 

  43. Schwarze, S.R., Ho, A., Vocero-Akbani, A. & Dowdy, S.F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569–1572 (1999).

    Article  CAS  Google Scholar 

  44. Borsello, T. et al. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat. Med. 9, 1180–1186 (2003).

    Article  CAS  Google Scholar 

  45. Liu, X.J. et al. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat. Med. 14, 1325–1332 (2008).

    Article  CAS  Google Scholar 

  46. Wong, T.P. et al. Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment. Proc. Natl. Acad. Sci. USA 104, 11471–11476 (2007).

    Article  CAS  Google Scholar 

  47. Goldberg, M.P. & Choi, D.W. Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J. Neurosci. 13, 3510–3524 (1993).

    Article  CAS  Google Scholar 

  48. Bederson, J.B. et al. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17, 472–476 (1986).

    Article  CAS  Google Scholar 

  49. Schmued, L.C., Albertson, C. & Slikker, W. Jr. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res. 751, 37–46 (1997).

    Article  CAS  Google Scholar 

  50. Park, H.J. et al. Role of sterol regulatory element binding proteins in the regulation of Gαi2 expression in cultured atrial cells. Circ. Res. 91, 32–37 (2002).

    Article  CAS  Google Scholar 

  51. Park, H.J. et al. Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP. J. Clin. Invest. 118, 259–271 (2008).

    Article  CAS  Google Scholar 

  52. Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).

    Article  CAS  Google Scholar 

  53. Lee, S.H. et al. Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319, 1253–1256 (2008).

    Article  CAS  Google Scholar 

  54. Mielke, J.G. & Wang, Y.T. Insulin exerts neuroprotection by counteracting the decrease in cell-surface GABA receptors following oxygen-glucose deprivation in cultured cortical neurons. J. Neurochem. 92, 103–113 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Ye (University of Texas Southwestern Medical Center) for myc–Insig-1 plasmid, T. Osborne (University of California–Irvine) for Flag–nt-SREBP-1 and Y. P. Auberson (Novartis Pharma AG) for the generous gift of NVP-AAM077. We also thank J. Wang for his technical support. This work was supported by the Heart and Stroke Foundation of British Columbia and the Yukon, the Canadian Institutes of Health Research and CHDI (Cure Huntington's Disease Initiative) Foundation. Y.T.W. is a Howard Hughes Medical Institute International Scholar and Heart and Stroke Foundation of British Columbia and the Yukon Chair in Stroke Research. C.T. was supported by post-doctoral fellowships from the Canadian Institutes of Health Research and Michael Smith Foundation for Health.

Author information

Author notes

  1. Changiz Taghibiglou and Henry G S Martin: These authors contributed equally to this work.

Authors and Affiliations

  1. Brain Research Centre and Department of Medicine, Coastal Health Research Institute, University of British Columbia, Vancouver, Canada

    Changiz Taghibiglou, Henry G S Martin, Ted Weita Lai, Taesup Cho, Shiv Prasad, Luba Kojic, Jie Lu, Yitao Liu, Edmund Lo, Shu Zhang, Julia Z Z Wu, Yu Ping Li, Yan Hua Wen, Joon-Hyuk Imm, Max S Cynader & Yu Tian Wang

  2. Center for Neuropsychiatry and Graduate Institute for Immunology, China Medical University Hospital, Taichung, Taiwan

    Yu Tian Wang

Authors
  1. Changiz Taghibiglou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henry G S Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ted Weita Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Taesup Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shiv Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luba Kojic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jie Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yitao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Edmund Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Julia Z Z Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yu Ping Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yan Hua Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Joon-Hyuk Imm
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Max S Cynader
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yu Tian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.T. initiated the study, wrote the manuscript and performed all biochemical experiments, H.G.S.M. performed most cell biology experiments and helped write the manuscript, T.W.L. performed the in vivo studies, T.C. and S.Z. contributed to the fluorescent microscopy, S.P., L.K. and Y.H.W. performed mRNA analysis and transcription factor screen, Y.L. aided in the in vivo studies, J.L. and J.Z.Z.W. designed and made Insig-1–specific antibody, E.L. aided in manuscript preparation, Y.P.L. and J.-H.I. prepared neuronal cultures and developed transfection methods, M.S.C. cosupervised the experiments of mRNA analysis transcription factor screen, and Y.T.W. designed the study and supervised the overall project.

Corresponding author

Correspondence to Yu Tian Wang.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 2150 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taghibiglou, C., Martin, H., Lai, T. et al. Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Nat Med 15, 1399–1406 (2009). https://doi.org/10.1038/nm.2064

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2064

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing