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K Stefansson

Publications and source records attributed to K Stefansson.

At least 37 records · Page 2Linked to original sources
PubMed1998

Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system.

The oligodendrocyte-myelin glycoprotein (OMgp) is a 110-kDa glycosylphosphatidylinositol-linked protein that was initially identified as a myelin-specific protein but whose precise function remains unknown. In this study, immunohistochemistry, western blots, in situ hybridization, and northern blots were used to determine the distribution of OMgp in the mouse brain. OMgp is present in a concentration detectable on western blots in the brains of newborn mice, and its concentration gradually increases until day 24 of life. OMgp mRNA is also present in amounts detectable on northern blots in the brains of newborn mice, and its concentration gradually increases until day 21 of life, after which the concentration diminishes a little. Most of the OMgp in the mouse brain appears to be expressed in diverse groups of neurons, but it is particularly prominent in large projection neurons such as the pyramidal cells of the hippocampus, the Purkinje cells of the cerebellum, motoneurons in the brainstem, and anterior horn cells of the spinal cord. However, OMgp is not confined to these cells and is expressed in cells in the white matter as well. The OMgp gene is placed within an intron of the neurofibromatosis type I gene and on the opposite strand. This organization raises the possibility that there may be a relationship between the functions of the products of the two genes. In support of this possibility, we show that within the mouse CNS OMgp and neurofibromin are expressed in the same cell types.

Aging↗
PubMed1998

Population genomics: laying the groundwork for genetic disease modeling and targeting.

The family has proven the most appropriate unit with which to study Mendelian diseases. There are, however, certain limitations on the use of the family as a fundamental unit in the study of common diseases, most of which are complex genetic diseases. The groups that are most likely to yield the genetics of complex diseases are isolated populations with strong founder effects. Therefore, access to such populations is proving to be a precious resource in the work on the genetics of common diseases. The Icelandic population is an excellent population for the study of the genetics of common diseases; it is genetically homogeneous, with founder effects for many traits, and the genealogy of the entire nation is well documented back to the founding days. Furthermore, the nature of the Icelandic national health care system facilitates the assignment of phenotypes in the search for disease genes. Decode Genetics has begun to study of the genetics of 20 of the most common diseases in the Western parts of the world. The company has placed the groundwork for the construction of an encrypted database with information on the health care of the entire nation, genealogy of the entire nation, genotyping information with high density of markers on a large part of the nation (including typing for known disease genes), and resource use in the Icelandic health care system. The plan is to build the database with approval of participating individuals as well as Icelandic government and health care officials. The database will be used to model health care as viewed in the context of genetic predisposition to the development of disease. The database will also be used in the search for drug targets in complex diseases and in the solution of pharmacogenomic problems. Basing the company in Iceland directly benefits the population in terms of employment and return on investment as well as providing the health care system with an information resource which may be used in preventive medicine and in the optimization of health care in Iceland.

Genealogy and Heraldry↗
PubMed1997

Beta-trace gene expression is regulated by a core promoter and a distal thyroid hormone response element.

We isolated and characterized the human beta-Trace protein (betaTP) gene promoter. betaTP, also known as prostaglandin D2 synthase, is a lipocalin secreted from the choroid plexus and meninges into cerebrospinal fluid. Basal transcription of the betaTP gene is directed from a core promoter found within the first 325 bases of the 5'-flanking sequence. The betaTP gene promoter is responsive to thyroid hormone (3,3',5-triiodothyronine, T3) and efficiently repressed by unliganded human thyroid hormone receptor beta (TRbeta). Functional analysis of the betaTP promoter in TE671 cells revealed that responsiveness to T3 occurs in sequences 2.5 kilobase pairs 5' of the start site. Within the hormone-responsive region we identified a thyroid hormone response element (TRE) located from -2576 to -2562 base pairs relative to the transcription start site. The betaTP TRE is composed of two directly repeated consensus half-sites separated by a 3-base pair space (DR3). The betaTP TRE forms specific complexes with TRbeta. We have shown that a gene active in the choroid plexus and meninges is responsive to T3. T3 may play a role in the regulated transport of substances into the cerebrospinal fluid and ultimately the brain.

Base Sequence↗
PubMed1996

Molecular evolution of tau protein: implications for Alzheimer's disease.

The brains of patients with Alzheimer's disease contain deposits of hyperphosphorylated tau proteins that have polymerized into insoluble fibrils. These deposits, in neurofibrillary tangles and dystrophic neurites, correlate with loss of cells and synapses, and consequently with dementia. Neurofibrillary pathology occurs in humans, as well as certain ungulates, including goats, sheep, and cows, but not in nonhuman primates. We hypothesize that the differences among species in the propensity to develop neurofibrillary pathology may be attributable to variations in the amino acid sequence of tau proteins. To investigate this hypothesis, we sequenced tau-encoding mRNA transcripts from the brains of rhesus monkey and domesticated goat and compared them with the known sequences of tau mRNAs from humans. The major difference we observed was that some tau mRNAs from rhesus monkey neocortex contain exon 8, whereas this exon has not been found in cortical tau from human or goat. Cows express very low levels of exon 8, and they tend to develop sparse neurofibrillary pathology with aging. We also found a transcribed tau-related pseudogene in rhesus monkey, which may be present in humans. We propose that differences in the expression of tau and tau-related protein sequences may underlie the predilection of human but not monkey brains to develop neurofibrillary degeneration.

Alzheimer Disease↗
PubMed1995

Focal brain injury and upregulation of a developmentally regulated extracellular matrix protein.

Tenascin is an extracellular matrix glycoprotein expressed during both normal development and neoplastic growth in both neural and nonneural tissues. During development of the central nervous system (CNS), tenascin is synthesized by glial cells, in particular by immature astrocytes, and is concentrated in transient boundaries around emerging groups of functionally distinct neurons. In the mature CNS, only low levels of the glycoprotein can be detected. The present study demonstrates that following trauma to the adult human cerebral cortex, discrete populations of reactive astrocytes upregulate their expression of tenascin and dramatically increase their transcription of the tenascin gene. The enhanced expression of tenascin may be involved in CNS wound healing, and may also affect neurite growth within and around a brain lesion.

Adult↗
PubMed1995

Nitric oxide synthase and guanylate cyclase levels in canine basilar artery after subarachnoid hemorrhage.

Endothelium-dependent vasodilation may be impaired during cerebral vasospasm following subarachnoid hemorrhage. Under normal circumstances nitric oxide (NO) released by endothelial cells induces relaxation of smooth muscle by activating the soluble form of guanylate cyclase within muscle cells. In this study the levels of both endothelial NO synthase, the enzyme that produces NO, and soluble guanylate cyclase were determined in canine basilar arteries in a double-hemorrhage model using Western blot immunoassays. Thirty dogs were assigned to three groups: Group D0, control; Group D2, dogs sacrificed 2 days after cisternal injection of blood; and Group D7, dogs given double cisternal injections of blood and sacrificed 7 days after the first injection. Constriction of the basilar artery was confirmed by arterial angiography. Portions of the affected arteries or the corresponding region in control animals were solubilized for sodium dodecylsulfate-polyacrylamide gel electrophoresis and Western blotting. A specific monoclonal antibody against endothelial NO synthase was used. The extract from basilar arteries showed two bands on the blots: 135 kD, characteristic of endothelial NO synthase, and 120 kD, which may be a degradation product of the enzyme. The densitometer values of the bands were presented as percentages of D0 control values. Although the total signal in the D7 group was less than that of the D0 control group (D2, 97% +/- 22%; D7, 78% +/- 40%), it was not statistically significant. The proportion of the 135-kD form decreased between Groups D0 and D7, but the difference was not significant. A single major band corresponding to the alpha-subunit of soluble guanylate cyclase was seen at 70 kD in the basilar artery extracts. The signals of D2 and D7 samples were 69% +/- 40% and 25% +/- 18%, respectively. There was a significant difference between D7 and D0 (p < 0.001). The reduced expression of soluble guanylate cyclase may be related to the impairment of endothelium-dependent vasodilation in vasospasm.

Amino Acid Oxidoreductases↗
PubMed1995

Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis.

BACKGROUND: The histopathology of multiple sclerosis (MS) is characterized by a loss of myelin and oligodendrocytes, relative preservation of axons, and a modest inflammatory response. The reasons for this selective oligodendrocyte death and demyelination are unknown. MATERIALS AND METHODS: In light of the T lymphocyte and macrophage infiltrates in MS lesions and the numerous cytokines these cells secrete, the direct influence of cytokines on survival of cultured oligodendrocytes and sensory neurons was investigated. Expression of cytokines in vivo was determined by immunolabeling cryostat sections of snap-frozen tissue containing chronic active lesions from four different patients. The samples were also analyzed for the presence of apoptotic nuclei by in situ labeling of 3'-OH ends of degraded nuclear DNA. RESULTS: The results showed: (i) interferon-gamma (IFN gamma) to be a potent inducer of apoptosis among oligodendrocytes in vitro and that this effect can be reversed by leukemia inhibitory factor (LIF); (ii) IFN gamma has a minimal effect on the survival of cultured neurons; (iii) IFN gamma at the margins of active MS plaques but not in unaffected white matter; (iv) evidence for apoptosis of oligodendrocytes at the advancing margins of chronic active MS plaques. CONCLUSIONS: Injury to a substantial number of oligodendrocytes in MS is the results of programmed cell death rather than necrotic cell death mechanisms. We postulate that IFN gamma plays a role in the pathogenesis of MS by activating apoptosis in oligodendrocytes.

Animals↗
PubMed1994

A role for the acetylcholine receptor-inducing protein ARIA in oligodendrocyte development.

ARIA acetylcholine receptor-inducing activity protein, is a member of a family of ligands that includes the Neu differentiation factor, heregulin, and glial growth factor. These ligands all act through one or more receptor tyrosine kinases of approximately 185 kDa. In some conditions these ligands promote proliferation, whereas in others they induce differentiation. ARIA was originally isolated from chick brain on the basis of its ability to induce synthesis of nicotinic acetylcholine receptors in skeletal muscle. In this paper we show that ARIA is expressed in the subventricular zone of the rat brain and that it enhances the development of oligodendrocytes from bipotential (O2A) glial progenitor cells. We have also found that ARIA induces tyrosine phosphorylation of a 185-kDa protein in O2A progenitor cells. ARIA does not increase bromodeoxyuridine incorporation by oligodendrocytes but is mitogenic when added to Schwann cells in vitro. Thus, ARIA accelerates the formation of oligodendrocytes in vitro and is expressed where it could exercise the same influence in vivo.

Animals↗
PubMed1994

Identification of Gal(beta 1-3)GalNAc bearing glycoproteins at the nodes of Ranvier in peripheral nerve.

A subset of human anti-GM1 ganglioside antibodies cross-reacts with Gal(beta 1-3)GalNAc bearing glycoproteins in peripheral nerve and spinal cord. The same oligosaccharide determinant is recognized by the lectin peanut agglutinin (PNA) which binds at the nodes of Ranvier in intact peripheral nerve. The Gal(beta 1-3)GalNAc bearing glycoproteins were isolated using PNA lectin affinity chromatography followed by separation on Western blot, and the proteins were subjected to partial amino acid sequence analysis. Two major PNA binding glycoproteins were identified in peripheral nerve and spinal cord; one had an approximate molecular weight of 120 kD and had sequence homology to the oligodendrocyte-myelin glycoprotein (OMgp). The other migrated between 70 and 80 kD and had sequence homology to the hyaluronate binding domain of versican, which has been reported to share sequence homology with the 70 kD proteins hyaluronectin and the glial hyaluronic acid binding protein (GHAP). By immunocytochemistry, OMgp was localized to the paranodal region of myelin, and the protein homologous to the hyaluronate binding domain of versican was localized to the nodal gap in peripheral nerve. These PNA binding glycoproteins might be target antigens for autoantibodies in peripheral nerve.

Amino Acid Sequence↗
PubMed1994

Inhibition of T cell activation by the extracellular matrix protein tenascin.

Tenascin (TN) is an extracellular matrix protein that is expressed widely in the fetus and sparingly in the adult, but reappears at high levels in certain areas of tissue insult such as tumor matrices and sites of wound healing. We show here that soluble TN inhibits proliferation of human T cells in response to alpha CD3 Ab co-immobilized with the extracellular matrix protein fibronectin (FN). TN also inhibits proliferation driven by alpha CD3/IL-2 or by phorbol ester/IL-2, and it prevents high level induction of IL-2R. The presence of TN in culture medium does not detectably alter the pattern of tyrosine phosphorylation resulting from T cell triggering with alpha CD3, but at later time points prevents the appearance of functional NF-AT1 transcription factor complexes in T cell nuclear extracts. These findings are consistent with the postulated role for TN as a natural antagonist to FN action, and suggest that T cell responses occurring at tissue sites in which TN is expressed could be influenced by its presence.

Base Sequence↗
PubMed1994

Expression of tenascin in thymus and thymic nonlymphoid cells.

Tenascin (TN) is an extracellular matrix glycoprotein that is widely expressed in fetal tissues and tumor matrices but is absent from most normal adult tissues. It is transiently expressed at sites of wound healing and has been shown to inhibit some types of T cell activation. We have examined the expression of TN in rat and human thymic tissue. Our results indicate that TN is expressed in both neonatal and adult rat thymus, and that in human thymus TN is present in a meshlike network at the corticomedullary junction. In addition, cultured human thymic non-lymphoid cells grown in serum-containing medium synthesize TN, whereas under serum-free conditions these cells secrete TN in response to transforming growth factor-beta.

Age Factors↗
PubMed1994

Is multiple sclerosis an autoimmune disease?

It is a commonly held view that multiple sclerosis (MS) may be an autoimmune disease. Most neurology texts list MS as an autoimmune disease and most texts on autoimmunity point to MS as a prime example of an autoimmune disease of the CNS. This view has influenced research into the pathogenesis of MS to the extent that most published work on MS is based on the assumption that it is correct, ignoring other possibilities, unless they can be put into an autoimmune context. Furthermore, most attempts at treating MS have been with agents that influence the immune system. Some of these agents, such as cytoxan and cyclosporin, are drugs with serious side-effects. Hence, it can be argued that over the years some MS patients have suffered because of the autoimmune hypothesis, although in the end and even today, other MS patients may benefit from it. This article examines some of the evidence in support of autoimmune hypotheses of the pathogenesis of MS. We believe that this examination shows that it has not been proven that MS is an autoimmune disease although it underscores the possibility that it may be so. Although it is still a reasonable hypothesis that MS is an autoimmune disease, it has yet to be proven and it would constitute a serious error of omission not to examine other possibilities.

Animals↗
PubMed1993

The oligodendrocyte-myelin glycoprotein of mouse: primary structure and gene structure.

The oligodendrocyte-myelin glycoprotein (OMgp), a phosphatidylinositol-linked membrane glycoprotein expressed in the brain, is in man encoded by a gene that is entirely within an intron of and on the strand opposite to the neurofibromatosis type 1 (NF1) gene. We obtained two distinct overlapping DNA clones from a mouse genomic library that contain the OMgp gene from mouse (mOMgp). There is a single intron in the 5' untranslated region in exactly the same position as the sole intron in the gene for the human OMgp (hOMgp). A repeat, (TC)24, in the mouse intron divides it into 5' and 3' segments that have 72 and 93% sequence identity, respectively, with the human gene. The deduced unprocessed polypeptides of both species have 440 amino acids and the similarity of the primary structures of mOMgp and hOMgp indicates conservation of function. The conservation of the nucleotide sequences of the coding, noncoding, and flanking regions of the two genes is remarkable and raises the possibility that the nucleotide sequence may serve a function that is separate from the role of encoding OMgp.

Amino Acid Sequence↗
PubMed1993

Mechanism of oxyhemoglobin-induced release of endothelin-1 from cultured vascular endothelial cells and smooth-muscle cells.

Release of endothelin-1 from cultured endothelial cells can be induced with oxyhemoglobin (oxyHb). The present study was conducted to explore whether oxyHb affects the release of endothelin-1 and the induction of endothelin-1 messenger ribonucleic acid (mRNA) and to examine the mechanism whereby oxyHb induces endothelin-1 production in cultured vascular smooth-muscle cells as well as in cultured endothelial cells. Oxyhemoglobin produces concentration-dependent (0.1 to 10 microM) and time-dependent (0 to 24 hours) increases in immunoreactive endothelin-1 in conditioned medium from bovine arterial endothelial cells. Oxyhemoglobin induces immunoreactive endothelin-1 in rat aortic smooth-muscle cells in the same fashion, although the rate is 30-fold less than that of endothelial cells. This promoting effect is much higher than that of other stimulators such as thrombin and phorbol 12-myristate 13-acetate. Northern blot analysis of total RNA from endothelial cells also showed endothelin-1 mRNA induction. Staurosporine, a protein kinase C (PKC) inhibitor, inhibited oxyHb-induced endothelin-1 production in both vascular endothelial and smooth-muscle cells, whereas an increase of intracellular cyclic adenosine monophosphate (cAMP) by forskolin or an addition of 8-bromo-cAMP only inhibited this effect in smooth-muscle cells. These findings suggest that oxyHb-induced endothelin-1 production in endothelial cells is regulated by PKC, and in smooth-muscle cells by both PKC and the cAMP-dependent pathway. The production of endothelin, the most potent vasoconstrictor, in both vascular endothelial and smooth-muscle cells by oxyHb may have significance in the pathogenesis of cerebral vasospasm.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Structure and chromosomal localization of the human gene for a brain form of prostaglandin D2 synthase.

We have cloned and characterized the human gene for the 21-kDa brain form of prostaglandin D2 synthase. The gene was isolated from a human genomic lambda library and spans 3600 base pairs. It consists of seven exons and six introns. Southern blot analysis indicates that there is a single copy of the gene in the haploid genome. The transcriptional start site was mapped to a G residue 74 base pairs 5' of the ATG initiation codon. A TATA box-like element (ATAAATA) is situated 21 base pairs upstream of the mRNA start site. The gene was mapped to chromosome 9 bands q34.2-q34.3. The gene bears close resemblance to the genes for murine major urinary protein and ovine beta-lactoglobulin.

Amino Acid Sequence↗
PubMed1992

Proligodendroblast antigen (POA), a developmental antigen expressed by A007/O4-positive oligodendrocyte progenitors prior to the appearance of sulfatide and galactocerebroside.

Evidence is presented for the immunological identification of a developmental antigen appearing at a critical point in the oligodendroglial lineage. Specifically, monoclonal antibody A007 recognizes cells in the oligodendrocyte lineage at two distinct stages. Analyses of purified lipid standards and lipid extracts from galactocerebroside-positive (GalC+) oligodendrocytes by enzyme-linked immunosorbent assay, lipid dot blot, and immuno-TLC demonstrated that A007 recognizes sulfatide (SUL) and seminolipid. However, neither 35SO4 incorporation into SUL nor SUL accumulation could be detected in A007-positive cells lacking galactocerebroside (i.e., A007+GalC- progenitor cells) present early in development. These data suggest that A007 also recognizes an antigen, named proligodendroblast antigen (POA), that appears during the late stage of oligodendrocyte progenitor development prior to the expression by oligodendrocytes of SUL and GalC. We have previously reported that monoclonal antibody O4 also recognizes not only SUL and seminolipid, but in addition an antigen that appears prior to the expression of SUL and galactocerebroside. In the present study all A007+ cells were also O4+ (and vice versa), and the developmental patterns of the two antibodies appeared to be identical. We conclude that (1) A007 is similar or identical to O4 with respect to its antigenic specificity, and (2) during oligodendrocyte lineage progression both antibodies react first with antigen POA on the surface of the oligodendrocyte progenitor cell prior to the expression of SUL [i.e., A007+O4+(POA+)SUL-GalC- proligodendroblasts], and only later with SUL as terminally differentiating oligodendrocytes emerge (i.e., A007+O4+SUL+GalC+ oligodendrocytes).

Animals↗