James E. Goldman, MD, PhD
Division of Anatomic Pathology
Division of Molecular Imaging and Neuropathology
Our lab is interested in CNS glial cell development, function, and pathology. We study the precursors of oligodendrocytes in the developing and adult CNS to understand how they repair myelin in the adult CNS and how they react to pathological conditions. We also study how astrocytes react to the presence of pathological changes and how pathological changes in astrocytes affect the other cells of the CNS.
We continue to study Alexander disease, a degenerative brain disorder caused by mutations in GFAP, the gene encoding the major astrocyte intermediate filament protein. These mutations activate intracellular stress responses and change the astrocyte phenotype dramatically. They lead to astrocyte dysfunction that resembles a marked reactive astrocytosis and produces pathology in neurons, oligodendrocytes, and microglia. Indeed, the major genes upregulated in Alexander disease are immune-function genes, which activate microglia, and produce electrophysiological changes in neurons. As a pure astrocyte disease, Alexander disease gives us insights into mechanisms of pathological changes in astrocytes in epilepsy, strokes, infections, and neoplasms and helps us understand how astrocytes influence the other cells of the CNS.
Large numbers of oligodendroyte progenitor cells (OPC) populate the adult CNS. What regulates their transition into mature and myelinating oligodendroytes (OL) is not well understood but is critical for developmental myelination, continued myelination in adulthood, and remyelination in demyelinating diseases. We have identified the CD82 tetraspanin molecule as a critical, positive, regulator of this transition. CD82 inhibits the HGF-c-met signaling pathway, the activation of which keeps OLs immature. In mature OLs downregulating CD82 activates c-met and causes the cells to revert to an immature stage. We are charactering the molecular changes that take place during this critical transition.
In collaboration with Guomei Tang and David Sulzer of Neurology, Guy McKhann of Neurosurgery, and Peter Sims of Systems Biology, we are studying the cellular and molecular changes in astrocytes and neurons that take place during the evolution of epilepsy and in the evolution of autistic-like behavior. Our collaborative group uses mouse models of Tuberous Sclerosis, a disease characterized by seizures and commonly by autism-spectrum disorders, in which cells have constitutively activated mTOR. RNASeq and ribosomal profiling and footprinting give us many genes that are transcriptionally regulated and also allow us to discover translationally-regulated gene expression.
Sosunov AA, McGovern RA, Mikell CB, Wu X, Coughlin DG, Crino PB, Weiner HL, Ghatan S, Goldman JE, McKhann GM. Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities. Acta Neuropathol Commun. 2015 Apr 2;3(1):17. doi: 10.1186/s40478-015-0191-5. PMID: 25853525.
Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A, Yue Z, Arancio O, Peterson BS, Champagne F, Dwork AJ, Goldman J, Sulzer D. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014 Sep 3;83(5):1131-43. doi: 10.1016/j.neuron.2014.07.040. Epub 2014 Aug 21. Erratum in: Neuron. 2014 Sep 17;83(6):1482. PMID: 25155956
Mayer JA, Griffiths IR, Goldman JE, Smith CM, Cooksey E, Radcliff AB, Duncan ID. Modeling the natural history of Pelizaeus-Merzbacher disease. Neurobiol Dis. 2015 Mar;75:115-30. doi: 10.1016/j.nbd.2014.12.023. Epub 2015 Jan 3. PMID: 25562656.
Collins-Praino LE, Francis YI, Griffith EY, Wiegman AF, Urbach J, Lawton A, Honig LS, Cortes E, Vonsattel JP, Canoll PD, Goldman JE, Brickman AM. Soluble amyloid beta levels are elevated in the white matter of Alzheimer's patients, independent of cortical plaque severity. Acta Neuropathol Commun. 2014 Aug 17;2:83. doi: 10.1186/PREACCEPT-3091772881321882. PMID: 25129614.
Walker AK, Daniels CM, Goldman JE, Trojanowski JQ, Lee VM, Messing A. Astrocytic TDP-43 pathology in Alexander disease. J Neurosci. 2014 May 7;34(19):6448-58. doi: 10.1523/JNEUROSCI.0248-14.2014. PMID: 24806671.
Sosunov AA, Wu X, Tsankova NM, Guilfoyle E, McKhann GM 2nd, Goldman JE. Phenotypic heterogeneity and plasticity of isocortical and hippocampal astrocytes in the human brain. J Neurosci. 2014 Feb 5;34(6):2285-98. doi: 10.1523/JNEUROSCI.4037-13.2014. PMID: 24501367.
Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K. Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J Neurosci. 2014 Feb 5;34(6):2231-43. doi: 10.1523/JNEUROSCI.1619-13.2014. PMID: 24501362.
Collins-Praino LE, Francis YI, Griffith EY, Wiegman AF, Urbach J, Lawton A, Honig LS, Cortes E, Vonsattel JP, Canoll PD, Goldman JE, Brickman AM. Soluble amyloid beta levels are elevated in the white matter of Alzheimer's patients, independent of cortical plaque severity. Acta Neuropathol Commun. 2014 Aug 17;2(1):83. doi: 10.1186/s40478-014-0083-0. PMID: 25927863.
Mela A, Goldman JE. CD82 blocks cMet activation and overcomes hepatocyte growth factor effects on oligodendrocyte precursor differentiation. J Neurosci. 2013 May 1;33(18):7952-60. doi: 10.1523/JNEUROSCI.5836-12.2013. PMID: 23637186.
Tang G, Gutierrez Rios P, Kuo SH, Akman HO, Rosoklija G, Tanji K, Dwork A, Schon EA, Dimauro S Goldman J, Sulzer D. Mitochondrial abnormalities in temporal lobe of autistic brain. Neurobiol Dis. 2013 Jun;54:349-61. doi: 10.1016/j.nbd.2013.01.006. Epub 2013 Jan 17. PMID: 23333625.
Sosunov AA, Guilfoyle E, Wu X, McKhann GM 2nd, Goldman JE. Phenotypic conversions of "protoplasmic" to "reactive" astrocytes in Alexander disease. J Neurosci. 2013 Apr 24;33(17):7439-50. doi: 10.1523/JNEUROSCI.4506-12.2013. PMID: 23616550.
Jang ES, Goldman JE. Pax6 expression is sufficient to induce a neurogenic fate in glial progenitors of the neonatal subventricular zone. PLoS One. 2011;6(6):e20894. doi: 10.1371/journal.pone.0020894. Epub 2011 Jun 17. PMID: 21698109.
Quan PL, Wagner TA, Briese T, Torgerson TR, Hornig M, Tashmukhamedova A, Firth C, Palacios G, Baisre-De-Leon A, Paddock CD, Hutchison SK, Egholm M, Zaki SR, Goldman JE, Ochs HD, Lipkin WI. Astrovirus encephalitis in boy with X-linked agammaglobulinemia. Emerg Infect Dis. 2010 Jun;16(6):918-25. doi: 10.3201/eid1606.091536. PMID: 20507741.
Tian R, Wu X, Hagemann TL, Sosunov AA, Messing A, McKhann GM, Goldman JE. Alexander disease mutant glial fibrillary acidic protein compromises glutamate transport in astrocytes.
J Neuropathol Exp Neurol. 2010 Apr;69(4):335-45. doi: 10.1097/NEN.0b013e3181d3cb52. PMID: 20448479.
Tang G, Perng MD, Wilk S, Quinlan R, Goldman JE. Oligomers of mutant glial fibrillary acidic protein (GFAP) Inhibit the proteasome system in alexander disease astrocytes, and the small heat shock protein alphaB-crystallin reverses the inhibition. J Biol Chem. 2010 Apr 2;285(14):10527-37. doi: 10.1074/jbc.M109.067975. Epub 2010 Jan 28. PMID: 20110364.
Mela A, 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. 2009 Sep 9;29(36):11172-81. doi: 10.1523/JNEUROSCI.3075-09.2009. PMID: 19741124.
Lin G, Mela A, Guilfoyle EM, Goldman JE. Neonatal and adult O4(+) oligodendro