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Glucocorticoid-Induced Leucine Zipper in Central Nervous System Health and Disease

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Abstract

The central nervous system (CNS) is a large network of intercommunicating cells that function to maintain tissue health and homeostasis. Considerable evidence suggests that glucocorticoids exert both neuroprotective and neurodegenerative effects on the CNS. Glucocorticoids act by binding two related receptors in the cytoplasm, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The glucocorticoid receptor complex mediates cellular responses by transactivating target genes and by protein: protein interactions. The paradoxical effects of glucocorticoids on neuronal survival and death have been attributed to the concentration and the ratio of mineralocorticoid to glucocorticoid receptor activation. Glucocorticoid-induced leucine zipper (GILZ) is a recently identified protein transcriptionally upregulated by glucocorticoids. Constitutively, expressed in many tissues including brain, GILZ mediates many of the actions of glucocorticoids. It mimics the anti-inflammatory and anti-proliferative effects of glucocorticoids but exerts differential effects on stem cell differentiation and lineage development. Recent experimental data on the effects of GILZ following induced stress or trauma suggest potential roles in CNS diseases. Here, we provide a short overview of the role of GILZ in CNS health and discuss three potential rationales for the role of GILZ in Alzheimer’s disease pathogenesis.

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Acknowledgements

We sincerely thank Bryan Maloney for critically reading of the manuscript. Investigator support for the study was provided by the following sources: NIA R01-AG051086, and Indiana Clinical & Translational Sciences Institute (ICTSI) and ISDH Spinal Cord and Brain Injury Board Fund (D.K. Lahiri), and 1R41AG053117-01 (MS and DKL).

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Authors and Affiliations

  1. Department of Oral Pathology, Medicine and Radiology, Indiana University School of Dentistry, Indianapolis, IN, USA

    Mythily Srinivasan

  2. Institute of Psychiatry Research, Department of Psychiatry and Medical & Molecular Genetics, School of Medicine, Indiana University–Purdue University Indianapolis, Indianapolis, IN, USA

    Debomoy K. Lahiri

  3. Indiana Alzheimer Disease Center (IADC), Neuroscience Research Center, 320 West 15th Street, NB 200C, Indianapolis, IN, 46202-2266, USA

    Debomoy K. Lahiri

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Correspondence to Mythily Srinivasan or Debomoy K. Lahiri.

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DKL serves on scientific advisory boards for QR Pharma, Yuma Therapeutics, Entia Biosciences, and Provaidya LLC and is a member of the Drug Discovery and Therapy World Congress. Editor in Chief, Current Alzheimer Research (Bentham Science).

Financial Disclosures

Stock options, QR Pharma; patent involving AIT-082, Memantine. Patents pending on acamprosate and patent involving GILZ analogs.

MS is the co-founder of the Provaidya LLC, Indianapolis, USA.

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The authors declare that they have no conflict of interest.

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Srinivasan, M., Lahiri, D.K. Glucocorticoid-Induced Leucine Zipper in Central Nervous System Health and Disease. Mol Neurobiol 54, 8063–8070 (2017). https://doi.org/10.1007/s12035-016-0277-5

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  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-0277-5

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