Research interests in my laboratory include 1) understanding the nature of progenitor cells in the adult CNS, and 2) glial cell pathology in neurodegenerative disorders.

1) We are currently studying a) the mechanisms by which astrocyte precursors control the numbers of cell divisions - this study has implications for our understanding of normal brain development and our understanding of astrocytic brain tumors, in which the normal controls on proliferation are missing; b) the molecular interactions that promote neuronal or glial development by radial glia; c) how stimulation of the epidermal growth factor promotes glial precursor cell division and migration and inhibits differentiation - this study has implications for the generation of brain tumors, many of which overexpress this growth factor receptor; d) the small populations of dividing cells in the adult CNS, which may serve as precursors to neurons and glia.

2) 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 dominant mutations in the GFAP gene. The accumulation of GFAP evokes a "stress" response in astrocytes and we are now studying the mechanisms by which this may occur. We are focusing on how mutated GFAP protein inhibits the proteasome (major protein- degrading organelle). This study has many implications for understanding the pathogenesis of a number of neurodegenerative diseases that are characterized by the abnormal accumulation of proteins in the cells’ cytoplasm. Working with astrocytes and mutant GFAP is an easily manipulated model system to study how protein accumulation damages cells. We can mimic the cytoskeletal protein abnormalities in tissue culture cells, and our collaborators are generating transgenic mice that express GFAP mutations. This may turn out to be 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. We are also studying how astrocytes in Alexander disease are toxic to neurons and to oligodendrocytes, the myelinating cells of the central nervous system.

Selected Recent Publications:

• Hsiao, VC, Tian, R, Long, H, Der Perng, M., Brenner, M, Quinlan, R., and Goldman, JE. Alexander disease mutation of GFAP causes filament disorganization and decreased solubility of GFAP protein. J.Cell Science, 118:2057-2065, 2005.
• Marshall, CAG, Novitch, B, and Goldman, JE: Olig2 directs astrocyte and oligodendrocyte formation in postnatal SVZ cells. J.Neurosci., 25:7289-7298, 2005.
• Tian, R., Gregor, M., Wiche, H., and Goldman, J.E.: Plectin regulates the organization of GFAP in Alexander Disease. Amer. J. Pathology, 168:888-897, 2006.
• 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., 281:38634-38643, 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, Messing A, Sulzer D, and Goldman JE: Alexander disease-mutant GFAP accumulation stimulates autophagy through p38 MAPK and mTOR signaling pathways. Hum Mol Genetics, 17:1540-1555, 2008.