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PubMed2006

Acute hypoxia and programmed cell death in developing CNS: Differential vulnerability of chick optic tectum layers.

The chick optic tectum displays an alternating pattern of cellular and plexiform layers and at embryonic day (ED) 12 there are mainly four cellular layers: transient cell compartment 3 (TCC3), compartment "h-i-j"(C"h-i-j"), stratum griseum centrale (SGC) and subventricular zone (SvZ). In the present work we characterized the programmed cell death (PCD) of these layers and their vulnerability to acute hypoxia at ED12, and also identified the main cellular type involved in hypoxic cell death. The colocalization of three independent markers of cell degeneration: pyknotic nuclei by Hoechst staining, fragmented DNA by TdT-mediated dUTP nick-end labeling (TUNEL), and presence of active caspase-3 by immunofluorescence, was analyzed in embryos that developed in normoxic conditions (control embryos) and embryos that were subjected to hypoxia (8% O(2)/92% N(2)) for 60 min (hypoxic embryos), followed by 0-12 h of normoxic recovery. In control embryos cell death rate within each layer was constant through time, but there were significant differences (P<0.01) in cell death rates among the different layers. In contrast, in hypoxic embryos, a significant increase (P<0.01) in cell death rate was observed in layers TCC3, C"h-i-j" and SGC. This change was evident only at 6 h post-hypoxia, and at later time points cell death rate was similar to control values. Each of these layers had a different vulnerability to the hypoxic event while the SvZ layer was not affected. In addition, the significant colocalization between the neuron specific nuclear protein (NeuN) and TUNEL signal showed that hypoxia affected primarily neurons. In conclusion, our findings demonstrate that in the chick optic tectum at ED12, PCD is layer dependent and that acute hypoxia causes a transient increase in neuronal death in a delayed fashion, which is also layer dependent. The morphological features of the neuronal death process at the light microscope level resembled apoptosis.

Analysis of Variance↗
PubMed2006

Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: possible roles in motor neuron survival.

In amyotrophic lateral sclerosis (ALS) there is a selective degeneration of motor neurons leading to muscle paralysis and death. The mechanism underlying cell demise in ALS is not fully understood, but involves the activation of different proteolytic enzymes, including the caspase family of cysteine proteases. We have here studied whether other proteases, such as the cathepsins, residing in lysosomes, and the cathepsin inhibitors, cystatinB and -C are changed in ALS. The expression and protein levels of the cathepsinB, -L and -D all increased in the spinal cord in ALS mice, carrying the mutant copper/zinc superoxide dismutase (SOD1) gene. At the cellular level, cathepsinB and -L were present in ventral motor neurons in controls, but in the ALS mice cathepsinB was also expressed by glial fibrillary acidic protein (GFAP) positive astrocytes. The distribution of the aspartic protease, cathepsinD also changed in ALS with a loss of the lysosomal staining in motor neurons. Inhibition of caspases by means of X-chromosome-linked inhibitor of apoptosis protein (XIAP) overexpression did not inhibit cleavage of cathepsinD in ALS mice, suggesting a caspase-independent pathway. Expression of cystatinB and -C increased slightly in the ALS spinal cords. Immunostaining showed that in ALS, cystatinC was present in motor neurons and in GFAP positive astrocytes. CystatinB that is a neuroprotective factor decreased in motor neurons in ALS but was expressed by activated microglial cells. The observed changes in the levels and distributions of cathepsinD and cystatinB and-C indicate a role of these proteins in the degeneration of motor neurons in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2002

A conformational epitope which detects autoantibodies from schizophrenic patients.

We previously found autoantibodies against platelets in schizophrenic patients. One of the platelet proteins that bind these antibodies is enolase. Here, we describe the isolation and sequencing of an immunoreactive peptide after enzymatic digestion of enolase. The 3-D structure of enolase indicates that, unexpectedly, this peptide is buried inside the protein. However, 3-D surface analysis leads to the identification of a conformational epitope that resembles the binding peptide and might constitute a specific binder of the autoantibodies. In a screening of antibody binding with the peptide LVVGLCK, we found in 50 serum samples of controls a mean of O.D.=0.46; s= +/- 0.21 relative enzyme immunoassay units, while in sera of 39 schizophrenic patients, we found a mean of O.D.=1.47; s= +/- 0.65; P<0.0001. Furthermore, an inverse correlation was observed between duration of schizophrenia and the level of the detected autoantibodies. A screening of autoantibodies in sera of various mental disorders with this peptide is currently in progress.

Adult↗
PubMed1997

Effect of site-directed mutagenesis of His373 of yeast enolase on some of its physical and enzymatic properties.

The X-ray structure of yeast enolase shows His373 interacting with a water molecule also held by residues Glu168 and Glu211. The water molecule is suggested to participate in the catalytic mechanism (Lebioda, L. and Stec, B. (1991) Biochemistry 30, 2817-2822). Replacement of His373 with asparagine (H373N enolase) or phenylalanine (H373F enolase) reduces enzymatic activity to ca. 10% and 0.0003% of the native enzyme activity, respectively. H373N enolase exhibits a reduced Km for the substrate, 2-phosphoglycerate, and produces the same absorbance changes in the chromophoric substrate analogues TSP1 and AEP1, relative to native enolase. H373F enolase binds AEP less strongly, producing a smaller absorbance change than native enolase, and reacts very little with TSP. H373F enolase dissociates to monomers in the absence of substrate; H373N enolase subunit dissociation is less than H373F enolase but more than native enolase. Substrate and Mg2+ increase subunit association in both mutants. Differential scanning calorimetric experiments indicate that the interaction with substrate that stabilizes enolase to thermal denaturation involves His373. We suggest that the function of His373 in the enolase reaction may involve hydrogen bonding rather than acid/base catalysis, through interaction with the Glu168/Glu211/H2O system, which produces removal or addition of hydroxyl at carbon-3 of the substrate.

Asparagine↗
PubMed1998

Mutant p53 may selectively suppress glial specific proteins in pluripotential human neuroectodermal tumor cells.

The p53 gene is mutated in pluripotential human neuroectodermal tumor DAOY cells which express both glial and neuronal markers. In most cells, nuclear m-p53 immunostaining was intense while cytoplasmic glial specific proteins (GSPs) were present at low levels. Conversely, glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) were expressed in the few cells devoid of nuclear m-p53 immunoreactivity. The level of neuron specific enolase (NSE) staining was low and not different between p53 positive and p53 negative cells. Therefore, a selective, mutually exclusive expression relationship exists between cytoplasmic GSPs and nuclear m-p53. Upon treatment with epidermal growth factor (EGF) and dibutyrylcyclic AMP, overall cytoplasmic GFAP and GS levels were increased while nuclear p53 was suppressed but a mutually exclusive expression pattern between these proteins was maintained. In cells which also express NSE, GFAP was selectively stimulated suggesting that nuclear expression of m-p53 and cytoplasmic expression of GSPs may be functionally related.

Cytoplasm↗
PubMed1995

14-3-3 proteins: structure resolved, functions less clear.

The crystal structures of 14-3-3 proteins reveal that they form dimers with a deep groove running along the length of the dimer. The location of conserved residues in this groove suggests that it plays an essential role in the adaptor functions of these proteins.

14-3-3 Proteins↗
PubMed1995

Glial cell line-derived neurotrophic factor promotes the survival and morphologic differentiation of Purkinje cells.

Glial cell line-derived neurotrophic factor (GDNF) promotes survival of midbrain dopaminergic neurons and motoneurons. Expression of GDNF mRNA in cerebellum raises the possibility that cells within this structure might also respond to GDNF. To examine potential trophic activities of GDNF, dissociated cultures of gestational day 18 rat cerebellum were grown for < or = 21 days in the presence of factor. GDNF increased Purkinje cell number without affecting the overall number of neurons or glial cells. A maximal response (50% above control) was elicited with GDNF at 1 pg/ml. Effects of GDNF on Purkinje cell differentiation were examined by scoring the morphologic maturation of cells in treated and control cultures. GDNF increased the proportion of Purkinje cells that displayed relatively mature morphologies, characterized by dendritic thickening and the development of spines and filopodial extensions. Morphologic maturation of the overall neuronal population was unaffected. In sum, our data indicate that GDNF is a potent survival and differentiation factor for Purkinje cells, the efferent neurons of cerebellar cortex. Together with its other actions, these findings raise the possibility that GDNF might be a critical trophic factor at multiple loci in neuronal circuits that control motor function.

Animals↗
PubMed1998

Cleavage motifs of the yeast 20S proteasome beta subunits deduced from digests of enolase 1.

The 436-amino acid protein enolase 1 from yeast was degraded in vitro by purified wild-type and mutant yeast 20S proteasome particles. Analysis of the cleavage products at different times revealed a processive degradation mechanism and a length distribution of fragments ranging from 3 to 25 amino acids with an average length of 7 to 8 amino acids. Surprisingly, the average fragment length was very similar between wild-type and mutant 20S proteasomes with reduced numbers of active sites. This implies that the fragment length is not influenced by the distance between the active sites, as previously postulated. A detailed analysis of the cleavages also allowed the identification of certain amino acid characteristics in positions flanking the cleavage site that guide the selection of the P1 residues by the three active beta subunits. Because yeast and mammalian proteasomes are highly homologous, similar cleavage motifs might be used by mammalian proteasomes. Therefore, our data provide a basis for predicting proteasomal degradation products from which peptides are sampled by major histocompatibility complex class I molecules for presentation to cytotoxic T cells.

Amino Acid Sequence↗
PubMedDate not supplied

The use of serum biomarkers to predict outcome after traumatic brain injury in adults and children.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in adults and children. Predicting outcome after TBI is difficult, but it is important for acute management, counseling of family members, and provision of rehabilitation services. Serum biomarkers may be useful alone or in combination with clinical variables to predict outcome after TBI. This article reviews the potential uses of serum biomarkers for the clinician, current literature related to the use of serum biomarkers for outcome prediction after adult and pediatric TBI, limitations of the literature, and future direction for this field.

Biomarkers↗
PubMed1997

Central neurocytoma arising within a mature cystic teratoma of the ovary.

Tumors of central nervous system elements are uncommon in cystic teratomas and tend to be derived from glial or primitive neuroectodermal cells. We describe the case of a 23-year-old woman with a central neurocytoma arising in an otherwise mature cystic teratoma of the ovary. Histologically, the neurocytoma was composed of collections of oligodendroglioma like cells in a fibrillary matrix. Cytologically the tumor was identical in appearance to central neurocytomas occurring within the adult brain. It expressed synaptophysin and neuron-specific enolase, confirming its neuronal lineage, but not glial fibrillary acidic protein. The site of the tumor recapitulated the typical location of neurocytomas adjacent to the lateral ventricle in that in abutted onto an ependyma-lined cyst within the teratoma. The patient remains well and free of tumor 1 year after cystectomy, in keeping with favorable follow-up data for surgically excised central neurocytomas within the brain.

Adult↗
PubMed1989

A study of 39 retinoblastomas with particular reference to morphology, cellular differentiation and tumour origin.

A series of 39 retinoblastomas was studied using light microscopy and immunohistochemistry for localization of neurone-specific enolase and glial fibrillary acidic protein. Thirty-eight retinoblastomas (97.4%) occurred in children less than 6 years of age: one was in a 61-year-old man (2.6%); the mean age, excluding the 61-year-old, was 32.1 months. Unilateral tumours were found in 74.4% of patients and bilateral tumours in 25.6%; bilateral lesions occurred in a younger age group, mean age of 21.7 vs 35.9 months. The male to female ratio was 1.4:1. Morphologically, arrangement of tumour cells into trabeculae was noted in 69.2% of retinoblastomas and glomerulus-like structures in 43.6%. These two patterns of cellular arrangement were encountered where the choroid and sclera were invaded by neoplastic cells. Homer Wright rosettes were observed in all tumours. Flexner-Winstersteiner rosettes in 33.3% and fleurettes in 2.6%. Differentiation into neoplastic neurones as well as in the form of Flexner-Winstersteiner rosettes and fleurettes was noted in 46.1%, neoplastic ependymal cells in 100.0%, astrocytes in 58.9%, oligodendrocytes in 23.1%, and glioblastomas in 2.6%. These data suggest that retinoblastoma is a primitive stem cell neuroectodermal tumour with the capacity for differentiation in both neuronal and neuroglial directions.

Aged↗
PubMed2005

Multimodal early onset stimulation combined with enriched environment is associated with reduced CNS lesion volume and enhanced reversal of neuromotor dysfunction after traumatic brain injury in rats.

This study was designed to determine whether exposure to multimodal early onset stimulation (MEOS) combined with environmental enrichment (EE) after traumatic brain injury (TBI) would improve neurological recovery and to elucidate its morphological correlates. Male Sprague-Dawley rats were subjected to lateral fluid percussion (LFP) brain injury or to sham operation. After LFP, one-third of the animals (injured and sham) were placed under conditions of standard housing (SH), one-third were kept in EE only, and one-third received EE + MEOS. Assessment of neuromotor function 24 h post-injury using a standardized composite neuroscore test revealed an identical pattern of neurological impairment in all animals subjected to LFP. Neuromotor dysfunction in SH animals remained on a similar level throughout the experiment, while improvements were noted in both other groups 7 days post-injury (dpi). On 15 dpi, reversal of neuromotor dysfunction was significantly better in EE + MEOS animals vs. SH- and EE-only groups. In parallel, the comparison of lesion volume in EE + MEOS- vs. EE-only vs. SH rats revealed that animals exposed to EE + MEOS had consistently the lowest values (mm3, mean +/- SD; n = 6 rats in each group) as measured in serial brain sections immunostained for neuron-specific enolase (5.2 +/- 3.4 < or = 5.5 +/- 4.1 < 9.5 +/- 1.9), caspase 3-active/C3A (5.9 +/- 4.0 < or = 6.4 +/- 3.9 < 10.3 +/- 1.8) and glial fibrillary acidic protein (6.0 +/- 3.4 < or = 6.5 +/- 4.3 < 10.7 +/- 1.2). This first report on the effect of EE + MEOS treatment strongly indicates that the combined exposure reduces CNS scar formation and reverses neuromotor deficits after TBI in rats.

Animals↗
PubMed2006

Targeted in utero delivery of a retroviral vector for gene transfer in the rodent brain.

In vivo application of viral vectors for gene transfer is a commonly used tool in anatomical and functional studies, as well as in development of neuroprotective and restorative strategies for therapy. Although the most common route of administration is via direct injection into the brain parenchyma in adult animals, a number of short-term studies have been performed in the developing central nervous system. Here we investigated the long-term transgene expression following in utero delivery of a retroviral vector encoding for the green fluorescent protein (GFP) marker gene at embryonic days 14.5-17.5 using an ultrasound-guided injection system. Intraparenchymal injections of the ganglionic eminence were compared with vector delivery to the intracerebroventricular space. Injections into the ganglionic eminences resulted in a predominantly unilateral transduction localized to the forebrain, giving rise to GFP-positive (GFP+) neurons and astrocytes in the striatum, olfactory bulb, cortex and hippocampus. When the vector was injected into the lateral ventricle, on the other hand, widespread expression of GFP was seen throughout the brain. The total number of GFP+ cells in the striatum was estimated to be between 20,000 and 50,000 cells using a computerized stereological quantification tool. Phenotypic characterization of these transduced cells using confocal microscopical analysis showed that 64% were NeuN+ neurons, 14% APC+ oligodendrocytes and 15% glial cells labelled with GFAP, S100beta and Iba1, when the vector injection was performed at E14.5. Delivery into later embryos resulted in a reduction in neuronal profiles with a reciprocal increase in glial cells.

Age Factors↗