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Biomedical subjects

J E Goldman

Publications and source records attributed to J E Goldman.

At least 19 recordsLinked to original sources
PubMed2002

A2B5+ and O4+ Cycling progenitors in the adult forebrain white matter respond differentially to PDGF-AA, FGF-2, and IGF-1.

Cycling glial progenitors reside within subcortical white matter of the mammalian adult forebrain. Either A2B5 or O4 expression defines two of the major classes of cycling progenitors. We examined the growth factor receptor profiles of these progenitor populations and their capability to proliferate and differentiate in response to PDGF-AA, FGF-2, and IGF-1. FGF-2 and IGF-1 enhance the acquisition of O1 by the O4+ progenitors, but have no significant effect on the acquisition of O4 and/or O1 by the A2B5+ progenitors. In contrast, PDGF-AA enhances the acquisition of O1 by the A2B5+ progenitors, while having no significant affect on the acquisition of O1 by the O4+ progenitors unless combined with FGF-2. In addition, PDGF-AA and FGF-2 promote the proliferation of A2B5+ progenitors, while having no mitogenic effect on the O4+ progenitors unless the two factors are combined with IGF-1. Interestingly, not all of the progenitors within the A2B5 or O4 populations express the same growth factor receptors nor respond similarly to growth factors. Thus, there are substantial differences between the two populations and heterogeneity within each of these populations may exist.

Animals↗
PubMed2001

Aldolase C/zebrin II expression in the neonatal rat forebrain reveals cellular heterogeneity within the subventricular zone and early astrocyte differentiation.

During late gestational and early postnatal development, proliferating cells in the subventricular zones of the lateral ventricles (SVZ) migrate into the gray and white matter of the forebrain and differentiate into astrocytes and oligodendrocytes. Because the cellular composition and structure of the neonatal SVZ is poorly understood, we performed a differential display PCR screen to identify genes preferentially expressed therein. One highly expressed gene encoded aldolase C. We used a specific monoclonal antibody, aldolase C/zebrin II (ALDC/ZII), in combination with markers of glial lineage and proliferation, to characterize the cells that express this gene. In the neonatal SVZ, ALDC/ZII-positive cells, which are generally polygonal and display several processes, have a nonuniform spatial distribution. They do not express vimentin, GFAP, or NG2. A subset of ALDC/ZII-positive cells incorporates bromodeoxyuridine, but progenitors identified by beta-galactosidase expression after infection with recombinant BAG virus do not show ALDC/ZII immunoreactivity. Outside of the SVZ, beta-galactosidase-positive/ALDC/ZII-positive cells have an astrocytic phenotype, suggesting that immunoreactivity was acquired after exit from the SVZ. These studies demonstrate that the neonatal SVZ is composed of different populations of cells that can be characterized by their antigenic phenotype, their proliferative capacity, and their spatial distributions. Nonrandom distributions of different cell types within the SVZ may permit the formation of microenvironments that stimulate the production of cells with specific potentials at appropriate points in development. Analysis of ALDC/ZII expression by astrocyte lineage cells in the neonatal cerebral cortex and white matter may reveal insights into the phenotype and behavior of undifferentiated astrocyte progenitors.

Animals↗
PubMed2001

Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.

Alexander disease is a rare disorder of the central nervous system of unknown etiology. Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation, leading to death usually within the first decade; patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. The pathological hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins. We previously found that overexpression of human GFAP in astrocytes of transgenic mice is fatal and accompanied by the presence of inclusion bodies indistinguishable from human Rosenthal fibers. These results suggested that a primary alteration in GFAP may be responsible for Alexander disease. Sequence analysis of DNA samples from patients representing different Alexander disease phenotypes revealed that most cases are associated with non-conservative mutations in the coding region of GFAP. Alexander disease therefore represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS.

Adolescent↗
PubMed2001

Alexander disease: new insights from genetics.

Prior to finding that GFAP mutations underlie many cases of Alexander disease, it was unclear whether the disease originated in astrocytes or if the formation of Rosenthal fibers was a response to an external insult. It was also unclear whether the etiology of the disease was environmental or genetic. For many cases of Alexander disease, these questions have now been answered. An immediate clinical benefit of this discovery is the possibility of diagnosing most cases of Alexander disease through analysis of patient DNA samples, rather than resorting to brain biopsy. In addition, fetal testing is now an option for parents who have had an Alexander disease child with an identified mutation and who wish to have additional children. For the future, these mutations should provide a unique window for illuminating the mechanism of the disease.

Brain↗
PubMed2001

Heterogeneity of cycling glial progenitors in the adult mammalian cortex and white matter.

The heterogeneity and differentiation potential of mitotically active cells in the adult brain were studied by labeling adult rats with BrdU, and isolating an enriched population of cycling cells from neocortex and from subcortical white matter. The majority of this population isolated from either brain region labeled with O4, an early oligodendrocyte marker. In tissue culture, these O4(+) progenitors acquired galactocerebroside, a glycolipid of mature oligodendrocytes, but not GFAP, an intermediate filament of astrocytes. A minority population expressed the intermediate filament protein, vimentin, but not O4. This population expressed GFAP after several days in culture. A third population of cycling cells, expressing the gangliosides labeled with the A2B5 antibody, represented a minority population in subcortical white matter, but one of the major cycling populations in cortex, with substantial overlap with O4. Small populations of cycling NG2(+) cells also were observed. Thus, the cycling cells in the adult brain are heterogeneous, and the majority appear to belong to glial lineages.

Age Factors↗
PubMed2000

AlphaB-crystallin regulates intermediate filament organization in situ.

AlphaB-crystallin is a small heat shock protein (hsp) and molecular chaperone that can interact with a wide spectrum of cellular components including intermediate filaments (IF). The significance of these interactions is not currently known. We have tested whether increased alphaB-crystallin expression effects changes in the IF systems in situ. Adenoviral-mediated gene transfer was used to overexpress alphaB-crystallin in primary astrocytes. A positive correlation was observed between overexpression of alphaB-crystallin and diffuse, filigree IF. AlphaB-crystallin did not appear to alter the polymerization state of IF proteins. These data show that an increase in alphaB-crystallin expression in the absence of stress can modify the organizational state of IF and that alphaB-crystallin can function as an IF debundling protein.

Adenoviridae↗
PubMed2000

Myoclonus from selective dentate nucleus degeneration in type 3 Gaucher disease.

OBJECTIVE: To describe a case with a new genetic variant of type 3 Gaucher disease presenting with stimulus-sensitive and action myoclonus in the presence of selective dentate abnormalities. DESIGN: Clinical, pathologic, and molecular genetic studies. SETTING: Medical school departments. PATIENT: A 6-year-old girl with type 3 Gaucher disease experienced progressively crippling generalized stimulus-sensitive and action myoclonus. Repeated electroencephalographic examination did not show cortical activity associated with the myoclonus, suggesting its subcortical origin. Neuropathological examination revealed selective degeneration of the cerebellar dentate nucleus and dentatorubrothalamic pathway in the face of essentially complete lack of storage in the brain. Mutation analysis identified the following 2 mutant alleles: one with a V394L mutation and the other with the lesion RecTL (D409H + L444P + A456P + V460V), which resulted from a recombination event, with the pseudogene located 16 kilobases downstream from the structural gene. CONCLUSION: Given the restricted abnormalities, this genetically unique case provides insight into the pathogenesis of myoclonus and suggests a prominent role for the cerebellar dentate nucleus in its genesis.

Cerebellar Nuclei↗
PubMed2000

Small heat shock proteins, the cytoskeleton, and inclusion body formation.

Since first being implicated in central nervous system disease 10 years ago, much has been learned concerning the regulation and function of the small heat shock protein alpha B-crystallin. Neuropathological, cellular and molecular studies all now point to a functional relationship between alpha B-crystallin and intermediate filaments. alpha B-crystallin accumulation marks reactive astrocytes in general in a wide variety of disorders and specifically intermediate filament-based glial inclusion bodies such as Rosenthal fibres found in astrocytes in Alexander's disease. In vitro, alpha B-crystallin expression suppresses intermediate filament aggregation and can prevent or reverse experimentally induced glial inclusion body formation. Conversely, dysregulation of glial fibrillary acidic protein expression in vivo results in Rosenthal fibre formation and upregulation of endogenous alpha B-crystallin expression. These data and those from studies recently carried out on other tissues strongly suggest that one function of this small heat shock protein is to modulate intermediate filament organization under conditions of physiological stress and neurodegenerative disease.

Animals↗
PubMed1999

Cycling cells in the adult rat neocortex preferentially generate oligodendroglia.

Gliogenesis in the mammalian central nervous system does not cease abruptly like neurogenesis. Instead, glia accumulate over a time period that extends into adulthood. To determine whether new glial cells in the adult cortex arise from resident progenitors and to determine the glial types to which these progenitors give rise to, cells in the perinatal subventricular zone (SVZ) were labeled with replication-deficient retroviral vectors, and clonal clusters of glia in the neocortex were examined from 1 week to 8 months of age. The average clonal cluster size increased during the first month of life. Interestingly, clusters containing oligodendrocyte lineage cells preferentially expanded with age, on average doubling every 3 months. Unexpectedly, the number of cells in astrocyte clusters decreased over time. In heterogeneous clusters, the numbers of oligodendroglia increased, whereas the number of astrocytes did not. Moreover, clonal clusters containing mature glia also contained less mature cells, indicating that clonally related progenitors do not differentiate synchronously in vivo. Thus, progenitors from the SVZ continue to cycle, resulting in an accumulation of oligodendroglia in the neocortex. These slowly cycling cells likely express the NG2 proteoglycan because a subset of the clonal clusters contained NG2(+) cells and these NG2(+) cells accumulated with time.

Animals↗
PubMed1999

A clinicopathological comparison of community-based and clinic-based cohorts of patients with dementia.

OBJECTIVES: To compare the sensitivity and specificity of the clinical diagnosis of Alzheimer disease, the distribution of pathological causes, and the demographic and clinical characteristics of 2 different groups of patients with dementia. DESIGN: Retrospective clinicopathological study. SETTING: A memory disorder clinic in a university hospital and a multiethnic community. PATIENTS: Sixty-three patients from a memory disorder clinic and 26 patients from a large community-based study who underwent autopsy after clinical evaluation. MAIN OUTCOME MEASURES: Differential distribution of clinical and pathological findings, with clinicopathological correlations. RESULTS: Clinic patients were younger at diagnosis, more educated, and more likely to be white. Of the 63 clinic patients we evaluated, 29 (46%) had a pathological diagnosis of definite AD, 15 (24%) had a diagnosis of mixed AD, and 19 (30%) had a diagnosis of another type of dementia. The pathological diagnoses in the community patients were distributed as follows: 6 (23%) had definite AD, 6 (23%) had mixed AD, 6 (23%) had cerebrovascular disease, and 8 (31%) had another type of dementia. The difference in distribution of pathological diagnoses between these 2 groups was only significant for cerebrovascular diseases. For patients seen at the clinic, the sensitivity of the clinical diagnosis of AD was 98% and the specificity was 84%; for the community group, the sensitivity was 92% and the specificity was 79%. CONCLUSIONS: The difference in sensitivity and specificity of clinical diagnosis was not statistically significant between the groups of clinic patients and community patients. Dementia associated with cerebrovascular disease was more prevalent in the community sample. This difference may be attributable to clinical and demographic differences between the 2 groups.

Age Factors↗
PubMed1999

Formation of GFAP cytoplasmic inclusions in astrocytes and their disaggregation by alphaB-crystallin.

In several neuropathological conditions, alphaB-crystallin and glial fibrillary acidic protein (GFAP) accumulate and form cytoplasmic inclusions in astrocytes. To explore the pathogenesis of the inclusions and the possible functions of the accumulated alphaB-crystallin, GFAP and alphaB-crystallin were overexpressed in cultured astrocytes by transient transfection. Human GFAP formed filamentous, cytoplasmic inclusions in mouse astrocytes, NIH3T3 cells, rat C6 glioma cells, and human U251 glioma cells. These human GFAP inclusions did not contain the endogenous vimentin or beta-tubulin, and the intermediate filament and microtubular networks of the transfected cells appeared normal. alphaB-crystallin and hsp25 were associated with the GFAP inclusions. Increasing intracellular alphaB-crystallin levels using recombinant adenoviruses, either before or after GFAP inclusions were formed, decreased the number of inclusion-bearing astrocytes and converted the human GFAP from an inclusion to a spread, filamentous form. These results suggest that alphaB-crystallin reorganizes abnormal intermediate filament aggregates into the normal filamentous network.

3T3 Cells↗
PubMed1999

Patterns and dynamics of SVZ cell migration in the postnatal forebrain: monitoring living progenitors in slice preparations.

Glial progenitors colonize the CNS widely in the perinatal period, but the pathways and mechanisms of migration are not well understood. We investigated the migration of progenitors from the neonatal rat forebrain subventricular zone (SVZ) by labeling them in vivo with a retrovirus encoding green fluorescent protein and visualizing movements by time lapse microscopy in slices. Cells within the dorsolateral SVZ moved in an undirected fashion but migrated radially and tangentially after emigration into white matter, cortex, and striatum. Cells in the striatal SVZ migrated parallel to the ventricular surface. During migration, elongation of the leading process and nuclear translocation were independent or linked. Orthogonal turning involved either cessation of cell body movement and formation of a new leading process or continuous cell body movement and bending of the leading process.

Animals↗
PubMed1999

Resistance of interleukin-1beta-deficient mice to fatal Sindbis virus encephalitis.

Interleukin-1beta (IL-1beta) concentrations are frequently elevated in central nervous system (CNS) viral infections, but the pathophysiologic significance of such elevations is not known. To examine the role of IL-1beta in CNS viral pathogenesis, we compared the natural histories of IL-1beta-deficient and wild-type 129 SV(ev) mice infected with a neurovirulent viral strain, neuroadapted Sindbis virus (NSV). We found that the incidence of severe paralysis and death was markedly decreased in NSV-infected IL-1beta-/- mice compared to NSV-infected wild-type mice (4 versus 88%, P < 0.001). Despite this marked difference in clinical outcome, no differences in numbers of apoptotic cells or presence of histopathologic lesions in the brains of moribund wild-type mice and those of clinically healthy IL-1beta-/- mice could be detected. These results suggest that IL-1beta deficiency is protective against fatal Sindbis virus infection by a mechanism that does not involve resistance to CNS virus-induced apoptosis or histopathology.

Alphavirus Infections↗
PubMed1998

Alpha B-crystallin is associated with intermediate filaments in astrocytoma cells.

Alpha B-crystallin, a major protein of the vertebrate lens and a member of the small heat shock protein family, is expressed in non-lenticular tissues, including the central nervous system, where it is found mainly in glia. In Rosenthal fibers (RF), astrocytic inclusions that accumulate in Alexander's Disease, alpha B-crystallin is found with hsp27 and skeins of intermediate filaments (IF) of the GFAP and vimentin types. We have investigated the association between IF and alpha B-crystallin in a human astrocytoma cell line, U-373MG, which expresses alpha B-crystallin. Cytoskeletal preparations contained alpha B-crystallin, and a filamentous pattern in which alpha B-crystallin co-localized with GFAP and vimentin by double label immunofluorescence. Immuno-electronmicroscopy confirmed the localization to IF. GFAP isolated from bovine brain and re-assembled, was associated with alpha B-crystallin. Thus, a proportion of alpha B-crystallin in astroglia is associated with IF, and this association may be critical in the formation of RF.

Animals↗
PubMed1998

Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein.

bcl-2, the prototypic cellular antiapoptotic gene, decreases Sindbis virus replication and Sindbis virus-induced apoptosis in mouse brains, resulting in protection against lethal encephalitis. To investigate potential mechanisms by which Bcl-2 protects against central nervous system Sindbis virus infection, we performed a yeast two-hybrid screen to identify Bcl-2-interacting gene products in an adult mouse brain library. We identified a novel 60-kDa coiled-coil protein, Beclin, which we confirmed interacts with Bcl-2 in mammalian cells, using fluorescence resonance energy transfer microscopy. To examine the role of Beclin in Sindbis virus pathogenesis, we constructed recombinant Sindbis virus chimeras that express full-length human Beclin (SIN/beclin), Beclin lacking the putative Bcl-2-binding domain (SIN/beclinDeltaBcl-2BD), or Beclin containing a premature stop codon near the 5' terminus (SIN/beclinstop). The survival of mice infected with SIN/beclin was significantly higher (71%) than the survival of mice infected with SIN/beclinDeltaBcl-2BD (9%) or SIN/beclinstop (7%) (P < 0.001). The brains of mice infected with SIN/beclin had fewer Sindbis virus RNA-positive cells, fewer apoptotic cells, and lower viral titers than the brains of mice infected with SIN/beclinDeltaBcl-2BD or SIN/beclinstop. These findings demonstrate that Beclin is a novel Bcl-2-interacting cellular protein that may play a role in antiviral host defense.

Alphavirus Infections↗