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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.

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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.

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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.

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  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

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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.

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Correspondence to Yu Tian Wang.

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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

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