James E. Goldman, M.D., Ph.D.Professor, Pathology and Cell Biology
Tel (212) 305-3554
Area of Research
Stem Cell Biology, Cell Specification and Differentiation, Neural Degeneration and Repair
Mammalian glial development, glial progenitors in the adult CNS; glial -neuronal interactions in degenerative disorders.
Research interests in my laboratory include 1) understanding the nature of progenitor cells in the developing and adult CNS, and 2) glial cell pathology in neurodegenerative disorders. The developing and adult mammalian brain contains populations of dividing cells, which serve as precursors to neurons and glia. We have been investigating the nature of these cycling cells, characterizing their phenotypes and the regulation of cell fate under normal and pathological circumstances. For example, cycling, immature cells in the adult white matter are stimulated to develop into myelinating oligodendrocytes after demyelination, thus contributing to the repair of the lesion.
We are studying glial reactions in pathological states, focusing upon specific proteins of astrocytes. Particular interests include GFAP, the major intermediate filament type in astrocytes, and the small heat shock protein, alpha B-crystallin, expressed in glial cells normally, but upregulated in pathological conditions. Massive amounts of crystallin and GFAP accumulate in the brains of children with Alexander's disease, a fatal CNS degenerative disorder, caused by point mutations in the GFAP gene. Alterations in cytoskeletal organization evoke a "stress" response in astrocytes and we are now studying the mechanisms by which this may occur. We can mimic the cytoskeletal protein abnormalities in tissue culture cells, and our collaborators have generated transgenic mice that express GFAP mutations. We have found that expression of the mutant GFAP will inhibit proteasome activity, stimulate MLK/JNK and p38 pathways, and stimulate autophagy in an mTOR-direction manner. Alexander astrocytes also decrease their expression of GLT-1, a major glutamate transporter in the CNS. This change has important implications for neuronal damage from excitotoxicity. Alexander disease is an excellent model for understanding fundamental reactions of cells to the abnormal aggregation of intracellular proteins, a pathological process found in a number of neurological disorders as well as illuminating the interactions between astrocytes and other CNS cells.
Marshall, CAG, Novitch, B, and Goldman, JE: Olig2 directs astrocyte and oligodendrocyte formation in postnatal SVZ cells. J.Neurosci., 25:7289-7298, 2005.
Tang G, Xu, Z, and Goldman, JE: Synergistic effects of the SAPK/JNK & the proteasome pathways on GFAP accumulation in Alexander disease. J. Biol. Chem., 50:38634-38643, 2006.
Ventura R and Goldman JE: Dorsal radial glia generate olfactory bulb interneurons in the postnatal murine brain. J. Neurosci. 27:4297-4302, 2007.
Ivkovic, S., Canoll, P., and Goldman, J.E. Constitutive EGFR signaling leads to glial progenitor hyperplasia in postnatal white matter. J. Neurosci., 28:914-922, 2008.
Tang G, Yue Z, Talloczy, Z, Hagemann T, Cho W, Sulzer D, Messing A, and Goldman JE: Alexander disease-mutant GFAP accumulation stimulates autophagy through p38 MAPK and mTOR signaling pathways. Hum Mol Genetics, 17:1540-1555, 2008.
Lin G and Goldman JE: Characterization of an FGF-responsive astrocyte precursor from the postnatal forebrain. Glia, 57:592-603, 2009.
Mela A and Goldman JE. The tetraspanin, KAI1/CD82, is expressed by late-lineage oligodendrocyte precursors and may function to restrict precursor migration and promote oligodendrocyte differentiation and myelination. J Neurosci, 29:11172-11181, 2009.
Lin G, Mela A, Guilfoyle EM, and Goldman JE. Neonatal and adult O4+ oligodendrocyte progenitors display different growth factor responses and different gene expression patterns. J Neurosci Res, 87:3390-3402.
Tang G, Der Perng M, Wilk S, Quinlan R, and Goldman JE. Oligomers of mutant GFAP inhibit the proteasome system in Alexander disease astrocytes, and the small heat shock protein, Alpha B-crystallin, reverses the inhibition, J Biol Chem, 285: 10777-10785, 2010.
Tian R, Wu X, Hagemann TL, Sosunov AA, Su Z-Z, Messing A, McKhann GM, and Goldman JE: Alexander disease mutant GFAP compromises glutamate transport in Alexander disease. J Neuropath Exp Neurol, 69:335-345, 2010.