James E. Goldman, MD, PhD

Research Summary
Neurodegenerative disorders

Our lab has been tracing cell lineages in the developing mammalian CNS to study the origins of neurons and glia from immature neuroectodermal cells. Using recombinant retroviruses to transfer genes into progenitor cells, we have followed the migration and differentiation of immature cells of germinal zones in vivo and have determined time- and location-specific patterns of glial development. We are examining what roles environmental vs. lineage-controlled factors play in specifying cell fates. We are particularly interested in how progenitors migrate through the developing brain, focusing on molecular mechanisms that regulate the direction, the beginning and the cessation of migration. Our lab is also starting to examine these same type of mechanisms as they apply to glial tumor migration through the brain.

We have also been studying responses of glial cells to pathological changes in the CNS. We are particularly interested in how the immature glia that reside in the adult CNS remyelinate axons after a demyelinating insult. We are also studying Alexander disease, a leukodystrophy in which the brain does not myelinate properly and astrocytes accumulate massive amounts of intermediate filaments and the small heat shock proteins, alpha ß-crystallin and hsp27. Recent studies show that Alexander disease is caused by mutations in the gene encoding GFAP, an intermediate filament expressed by astrocytes. We are studying how these mutations result in the accumulation of filaments, an accompanying astrocyte stress response, and the inability of the brain to myelinate properly.

1. Messing, A., Head, M.W., Galles, K., Galbreath, E.J., Goldman, J.E., and Brenner, M. Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am. J. Pathol. 152: 391-398 (1998).

2. Koyama, Y. and Goldman, J.E.: Formation of GFAP inclusions in astrocytes and their disaggregation by ?ß-crystallin. Am. J. Pathol., 154: 1563-1572 (1999).

3. Levison, S.W.; Young, G.M.; and Goldman, J.E.: Cycling cells in the adult rat neocortex produce oligodendrocytes. J. Neurosci. Res., 57: 435-446 (1999).

4. Kakita, A. and Goldman, J.E.: Patterns and dynamics of SVZ cell migration in the postnatal forebrain: monitering living progenitors in slice preparations. Neuron, 23: 461-472 (1999).

5. Brenner, M., Johnson, A.B., Boespflug-Tanguy, O., Rodriguez, D., Goldman, J.E. and Messing, A. Mutations in glial fibrillary acidic protein (GFAP) associated with Alexander disease. Nature Genetics, 27: 117-120 (2001).

6. Staugaitis, S.M., Zerlin, M., Levine, J.M., Hawkes, R., and Goldman, J.E.: Aldolase C/Zebrin II expression in neonatal rat forebrain reveals cellular heterogeneity within the subventricular zone and early astrocyte differentiation. J. Neurosci., 21: 6195-6205 (2001).

1. Cellular & Biochemical Studies Central Nervous System Glia
Our laboratory has been examining the genesis of astrocytes and oligodendrocytes during early CNS development and the nature and differentiation potential of immature glial cells in the adult CNS.
National Institute of Neurological Disorders and Stroke
7/1/89-6/30/2004

2. Cellular pathology of Alexander Disease
We propose to examine several aspects of intermediate filament (IF) organization and cellular stress reactions that may be germane to an understanding of the pathophysiology of Alexander disease. These experiments will focus on how the accumulation of a protein in one cell type (Astrocytes) appears to produce deleterious effects on another cell type (oligodendrocytes), the rationale taken from experiments in which cytokines are toxic to oligodendrocytes.
National Institute of Neurological Disorders and Stroke

cellular pathology, gene expression, intermediate filament, leukodystrophy, stimulus /response, astrocyte, cell differentiation, complementary DNA, free radical oxygen, gene mutation, genetic transcription, genetic translation, heat shock protein, mitogen activated protein kinase, myelination, neuropathology, oligodendroglia, gel electrophoresis, human tissue, immunocytochemistry, laboratory rat, northern blotting, tissue /cell culture, transfection, western blotting