Neurology

  • Description

        The Division of Neurochemistry and Neurobiology, directed by Dr. Asgar Zaheer, provides bench-side research opportunities for members of the Department (faculty, residents, medical students, postdoctoral and pre-doctoral fellows), as well as undergraduate and graduate students, to explore various biochemical, molecular and cellular aspects of neurology in health and disease. Research facilities include tissue culture setup; light, phase-contrast, and fluorescence microscopy; and biochemical and molecular biology equipment. Emphasis has been placed on the characterization of novel brain proteins and the elucidation of their biological functions in the nervous system.

        Current work centers on the study of glia maturation factor (GMF) which is a unique, endogenous brain protein that was isolated, sequenced and cloned in our laboratory. Recent study focuses on GMF as an intracellular signal transduction regulator. In vitro, GMF can be phosphorylated by PKC, PKA, CKII and RSK, and PKA-phosphorylated GMF is an inhibitor of the ERK isoform of MAP kinase while at the same time a stimulator of the p38 isoform, implicating the involvement of GMF in stress-activated response. Overexpression of GMF (with an adenovirus/GMF construct) in C6 glioma cells brings out differentiated characteristics and slows down tumorigenicity, along with the activation of the antioxidant enzyme superoxide dismutase (SOD) and the anti-apoptotic transcription factor NF-kB. In addition, overexpression of GMF by C6 cells promotes the expression and secretion of neurotrophic factors, in particular NGF and BDNF. That these factors are indeed biologically active is evident in the ability of the GMF-transfected C6 conditioned medium to promote neurite outgrowth in PC12 cells and the survival of cerebellar granule cells. Overexpression of GMF in PC12 pheochromocytoma cells activates p38 MAP kinase, its downstream kinase MAPKAP-K2, and the downstream effector tyrosine hydroxylase, accompanied by an increased phosphorylation of these proteins. Overexpression of GMF in normal astrocytes results in the activation of p38 MAP kinase and the transcription factors CREB and NF-k B, along with an increased production of NGF and BDNF. Using the DNA microarray technology, we have shown that GMF stimulates astrocytes to produce and secret proinflammatory cytokines such as GM-CSF and TNFα which are capable of immune activation through stimulation of microglia. It thus appears that although under normal conditions GMF is capable of neuroprotection including neuronal survival and the combat of infection, under abnormal situations GMF may aggravate autoimmune diseases such as multiple sclerosis. Likewise, GMF may also be involved in the pathophysiology of Alzheimer’s disease since microglial activation is known to contribute to the inflammatory reaction in the neuritic plaques. Our new findings thus open up new avenues of inquiry into autoimmune and degenerative neurologic diseases and may suggest new therapeutic interventions. We are currently pursuing these goals. Recent development in our lab includes the successful creation of GMF knockout mice. A number of projects are going on using this powerful tool for the study of GMF function.


    Recent Publications:

    • R. Lim and A. Zaheer: Phorbol ester stimulates rapid intracellular phosphorylation of glia maturation factor, Biochem. Biophys. Res. Comm., 211, 928-934 (1995).
    • A. Zaheer, W. Zhong and R. Lim: Expression of mRNAs of multiple growth factors and receptors by neuronal cell lines: detection with RT-PCR, Neurchem. Res., 20, 1457-1463 (1995).
    • C.M. Palatucci, Z.L. Fulop, R. Lim and D.G. Stein: Infusion of glia maturation factor reduces behavioral deficits after caudate nucleus injury in rats, Intern J. Neuroscience, 84, 135-147 (1996).
    • A. Zaheer and R. Lim: In vitro inhibition of MAP kinase (ERK1/ERK2) activity by phosphorylated glia maturation factor (GMF), Biochemistry, 35, 6283-6288 (1996).
    • R. Lim and A. Zaheer: In vitro enhancement of p38 MAP kinase activity by phosphorylated glia maturation factor (GMF), J. Biol. Chem., 271, 22953-22956 (1996).
    • A. Zaheer and R. Lim: PKA- and PKC-phosphorylated glia maturation factor (GMF) promotes the catalytic activity of protein kinase A, J. Biol. Chem., 272, 5183-5186 (1997).
    • R. Lim, A. Zaheer, J.A. Kraakevik, C.J. Darby and L.W. Oberley: Overexpression of glia maturation factor in C6 cells promotes differentiation and activates superoxide dismutase, Neurochem. Res., 23,1445-1451 (1998).
    • A. Zaheer and R. Lim: Overexpression of glia maturation factor (GMF) in PC12 pheochromocytoma cells activates p38 MAP kinase, MAPKAP kinase-2, and tyrosine hydroxylase, Biochem. Biophys. Res. Comm. 250, 278-282 (1998).
    • A. Zaheer, J. L. Weiss, P. Goyal and R. Lim: Enhanced expression of neurotrophic factors by C6 cells after transfection with glia maturation factor (GMF), Neurosci. Lett., 265, 203-206 (1999).
    • W. Zhong, T. Yan, R. Lim and L.W. Oberley: Expression of superoxide dismutase, catalase, and glutathione peroxidase in glioma cells. Free Radical Biol. & Med., 27, 1334-1345 (1999).
    • R. Lim, A. Zaheer, M.A. Yorek, C.J. Darby and L.W. Oberley: Activation of NF-k B in C6 rat glioma cells after transfection with glia maturation factor (GMF), J. Neurochem., 74, 596-602 (2000).
    • N.J. Pantazis, A. Zaheer, D. Dai, S. Zaheer, S.H., Green and R. Lim: Transfection of C6 glioma cells with glia maturation factor upregulates BDNF and NGF : trophic effects and protection against ethanol toxicity in cerebellar granule cells, Brain Res., 865, 59-76 (2000).
    • A. Zaheer, M..A. Yorek and R. Lim: Effects of glia maturation factor overexpression in primary astrocytes on MAP kinase activation, transcription factor activation, and neurotrophin secretion, Neurochem. Res., 26, 1293-1299 (2001).
    • A. Zaheer , S.N. Mathur and R. Lim: Overexpression of glia maturation factor in astrocytes leads to immune activation of microglia through secretion of granulocyte-macrophage-colony stimulating factor, Biochem. Biophys. Res. Comm., 294, 238-244 (2002).