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Selected AbstractsNovel mutation in the ceruloplasmin gene causing a cognitive and movement disorder with diabetes mellitusMOVEMENT DISORDERS, Issue 12 2006Hui-Fang Shang MD Abstract In a Chinese woman who had diabetes mellitus, undetectable ceruloplasmin, hand tremor, neck dystonia, and cognitive disturbances, genetic analyses revealed a novel homozygous mutation (848G>C or W283S) in exon 5 in the ceruloplasmin gene. Another member with a milder phenotype was also affected by this mutation. The healthy sister was heterozygous at the same position. Aceruloplasminemia has not yet been reported in China. This case suggests that increased awareness should be paid to this disorder in the presence of the typical symptoms. © 2006 Movement Disorder Society [source] Neuroprotective effect of interleukin-6 and IL6/IL6R chimera in the quinolinic acid rat model of Huntington's syndromeEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2001Jean-Charles Bensadoun Abstract Ciliary neurotrophic factor prevents behavioural deficits and striatal degeneration in rat and primate models of Huntington's disease. Interleukin-6, another member of the cytokine family, and the chimeric molecule (IL6/IL6R) in which interleukin-6 and its soluble receptor are fused, have been shown to exert trophic action on various neuronal populations in the central nervous system. Therefore, we investigated the neuroprotective effect of these two molecules in the quinolinic acid model of Huntington's disease. LacZ-, interleukin-6- and IL6/IL6R-expressing lentiviral vectors were stereotaxically injected into the striatum of Wistar rats. Three weeks later the animals were lesioned through the intrastriatal injection of 180 nmol of quinolinic acid. The extent of the striatal damage was significantly diminished in the rats that had been treated with interleukin-6 or IL6/IL6R. The neuroprotective effect was, however, more pronounced with the IL6/IL6R chimera than with interleukin-6 as indicated by the volume of the lesions (38.6 ± 10% in the IL6/IL6R group, 63.3 ± 3.6% in the IL-6 group and 84.3 ± 2.9% in the control group). Quantitative analysis of striatal interneurons further demonstrated that the IL6/IL6R chimera is more neuroprotective than IL-6 on ChAT- and NADPH-d-immunoreactive neurons. These results suggest that the IL6/IL6R chimera is a potential treatment for Huntington's disease. [source] Targeted Expression of SHH Affects Chondrocyte Differentiation, Growth Plate Organization, and Sox9 Expression,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2004Sara Tavella Abstract The role of Hedgehogs (Hh) in murine skeletal development was studied by overexpressing human Sonic Hedgehog (SHH) in chondrocytes of transgenic mice using the collagen II promoter/enhancer. Overexpression caused a lethal craniorachischisis with major alterations in long bones because of defects in chondrocyte differentiation. Introduction: Hedgehogs (Hhs) are a family of secreted polypeptides that play important roles in vertebrate development, controlling many critical steps of cell differentiation and patterning. Skeletal development is affected in many different ways by Hhs. Genetic defects and anomalies of Hhs signaling pathways cause severe abnormalities in the appendicular, axial, and cranial skeleton in man and other vertebrates. Materials and Methods: Genetic manipulation of mouse embryos was used to study in vivo the function of SHH in skeletal development. By DNA microinjection into pronuclei of fertilized oocytes, we have generated transgenic mice that express SHH specifically in chondrocytes using the cartilage-specific collagen II promoter/enhancer. Transgenic skeletal development was studied at different embryonic stages by histology. The expression pattern of specific chondrocyte molecules was studied by immunohistochemistry and in situ hybridization. Results: Transgenic mice died at birth with severe craniorachischisis and other skeletal defects in ribs, sternum, and long bones. Detailed analysis of long bones showed that chondrocyte differentiation was blocked at prehypertrophic stages, hindering endochondral ossification and trabecular bone formation, with specific defects in different limb segments. The growth plate was highly disorganized in the tibia and was completely absent in the femur and humerus, leading to skeletal elements entirely made of cartilage surrounded by a thin layer of bone. In this cartilage, chondrocytes maintained a columnar organization that was perpendicular to the bone longitudinal axis and directed toward its outer surface. The expression of SHH receptor, Patched-1 (Ptc1), was greatly increased in all cartilage, as well as the expression of parathyroid hormone-related protein (PTHrP) at the articular surface; while the expression of Indian Hedgehog (Ihh), another member of Hh family that controls the rate of chondrocyte maturation, was greatly reduced and restricted to the displaced chondrocyte columns. Transgenic mice also revealed the ability of SHH to upregulate the expression of Sox9, a major transcription factor implicated in chondrocyte-specific gene expression, in vivo and in vitro, acting through the proximal 6.8-kb-long Sox9 promoter. Conclusion: Transgenic mice show that continuous expression of SHH in chondrocytes interferes with cell differentiation and growth plate organization and induces high levels and diffuse expression of Sox9 in cartilaginous bones. [source] Isoprostane 8-epi-PGF2, is frequently increased in patients with muscle pain and/or CK-elevation after HMG-Co-enzyme-A-reductase inhibitor therapyJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2001H. Sinzinger Background:,Muscle pains with or without CK-elevation are among the most frequently observed side-effects in patients with hyperlipoproteinemia on various statins. The pathophysiological background, however, remains obscure. Methods:,We examined isoprostane 8-epi-PGF2,, a marker of in-vivo oxidation injury, in plasma, serum and urine in these patients at baseline, when muscle problems manifested and different time intervals after withdrawing the respective statin. A healthy control group and a group of untreated patients with hyperlipoproteinemia were run as controls. Results:,The majority of patients with muscular side-effects show elevated 8-epi-PGF2, in plasma and urine, whereas serum values were elevated only to a lesser extent. Stopping statin therapy or successfully changing to another member of this family of compounds resulted in a normalization of the values in all patients. Conclusion:,These findings indicate a significant involvement of oxidative injury in the muscular side-effects of statins in patients suffering from hyperlipoproteinemia. [source] The C-terminal C1 cassette of the N -methyl- d -aspartate receptor 1 subunit contains a bi-partite nuclear localization sequenceJOURNAL OF NEUROCHEMISTRY, Issue 6 2002K. D. Holmes Abstract The N -methyl- d -aspartate receptor (NMDAR) is a multimeric transmembrane protein composed of at least two subunits. One subunit, NR1, is derived from a single gene and can be subdivided into three regions: the N-terminal extracellular domain, the transmembrane regions, and the C-terminal intracellular domain. The N-terminal domain is responsible for Mg2+ metal ion binding and channel activity, while the transmembrane domains are important for ion channel formation. The intracellular C-terminal domain is involved in regulating receptor activity and subcellular localization. Our recent experiments indicated that the intracellular C-terminal domain, when expressed independently, localizes almost exclusively in the nucleus. An examination of the amino acid sequence reveals the presence of a putative nuclear localization sequence (NLS) in the C1 cassette of the NR1 intracellular C-terminus. Using an expression vector designed to test whether a putative NLS sequence is a valid, functional NLS, we have demonstrated that a bi-partite NLS does in fact exist within the NR1-1 C-terminus. Computer algorithms identified a putative helix,loop,helix motif that spanned the C0C1 cassettes of the C-terminus. These data suggest that the NR1 subunit may represent another member of a family of transmembrane proteins that undergo intramembrane proteolysis, releasing a cytosolic peptide that is actively translocated to the nucleus leading to alterations in gene regulation. [source] The red-ox status of a penicillin-binding protein is an on/off switch for spore peptidoglycan synthesis in Bacillus subtilisMOLECULAR MICROBIOLOGY, Issue 1 2010Patrick Eichenberger Summary Thiol-disulphide oxidoreductases catalyse the formation or breakage of disulphide bonds to control the red-ox status of a variety of proteins. Their activity is compartmentalized, as exemplified by the distinct roles these enzymes play in the cytoplasm and periplasm of Gram-negative bacteria. In this issue of Molecular Microbiology, an article from Lars Hederstedt and collaborators at Lund University sheds light on another member of this superfamily of proteins, the thioredoxin-like protein StoA from Bacillus subtilis. Interestingly, StoA function is required in yet another subcellular compartment: the intermembrane space that separates forespores from mother cells in endospore-forming bacteria. Specifically, this study demonstrates that the high-molecular-weight penicillin-binding protein SpoVD, which contains two exposed cysteine residues and whose extracellular domain is located in the intermembrane space, is a substrate of StoA. As formation of a disulphide bond most likely inactivates SpoVD activity, the converse breakage of that bond in a process catalysed by StoA appears to be the trigger that initiates peptidoglycan synthesis in sporulating cells. [source] Immunohistochemical parcellation of the ferret (Mustela putorius) visual cortex reveals substantial homology with the cat (Felis catus)THE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 21 2010Jihane Homman-Ludiye Abstract Electrophysiological mapping of the adult ferret visual cortex has until now determined the existence of 12 retinotopically distinct areas; however, in the cat, another member of the Carnivora, 20 distinct visual areas have been identified by using retinotopic mapping and immunolabeling. In the present study, the immunohistochemical approach to demarcate the areal boundaries of the adult ferret visual cortex was applied in order to overcome the difficulties in accessing the sulcal surfaces of a small, gyrencephalic brain. Nonphosphorylated neurofilament (NNF) expression profiles were compared with another classical immunostain of cortical nuclei, Cat-301 chondroitin sulfate proteoglycan (CSPG). Together, these two markers reliably demarcated the borders of the 12 previously defined areas and revealed further arealization beyond those borders to a total of 19 areas: 21a and 21b; the anterolateral, posterolateral, dorsal, and ventral lateral suprasylvian areas (ALLS, PLLS, DLS, and VLS, respectively); and the splenial and cingulate visual areas (SVA and CVA). NNF expression profile and location of the newly defined areas correlate with previously defined areas in the cat. Moreover, NNF and Cat-301 together revealed discrete expression domains in the posteroparietal (PP) cortex, demarcating four subdivisions in the caudal lateral and medial domains (PPcL and PPcM) and rostral lateral and medial domains (PPrL and PPrM), where only two retinotopic maps have been previously identified (PPc and PPr). Taken together, these studies suggest that NNF and Cat-301 can illustrate the homology between cortical areas in different species and draw out the principles that have driven evolution of the visual cortex. J. Comp. Neurol. 518:4439,4462, 2010. © 2010 Wiley-Liss, Inc. [source] | |||||||||||||