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PubMed2002

ATP and UTP excite sensory neurons and induce CREB phosphorylation through the metabotropic receptor, P2Y2.

Extracellular ATP rapidly excites nociceptive sensory neurons by opening ATP-gated ion channels (P2X receptors). Here, we describe two actions of both ATP and UTP on rat sensory neurons that are relatively slow and sustained: phosphorylation of the transcription factor CREB and delayed action potential firing that persists for tens of seconds after removal of the ligand. The pharmacology of these responses indicates that they are mediated by the metabotropic receptor P2Y2, and not by P2X receptors. CREB phosphorylation occurred in a subset of small peripherin-positive neurons likely to be unmyelinated nociceptors. In situ hybridization analysis revealed widespread expression of P2Y2 mRNA in sensory neurons. CREB phosphorylation is mediated by both action-potential-evoked calcium influx and calcium release from intracellular stores. These findings suggest that P2Y2 contributes to the transduction of ATP-mediated sensory signalling, and may be involved in the activity-dependent regulation of nociceptor phenotype.

Action Potentials↗
PubMed2003

Catecholamine-independent transient expression of tyrosine hydroxylase in primary auditory neurons is coincident with the onset of hearing in the rat cochlea.

During the last stages of neuronal maturation, tyrosine hydroxylase is transiently expressed in the absence of the other catecholamine-synthesizing enzymes. We show here that it is expressed in rat spiral ganglion neurons between postnatal days 8 and 20, with a peak of expression at postnatal day 12. These tyrosine hydroxylase-immunoreactive neurons did not display aromatic amino acid decarboxylase- or dopamine-beta-hydroxylase-immunoreactivities, ruling out the possibilities of dopamine or noradrenaline synthesis. They also did not display peripherin- or intense neurofilament 200-kDa-immunoreactivities, two indicators of type II primary auditory neurons. Tyrosine hydroxylase-immunoreactive dendrites were seen in synaptic contact with the inner hair cells and expressed the GluR2 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, further confirming the type I nature of the neurons transiently expressing the enzyme. The end of the tyrosine hydroxylase expression was not due to cell death because the immunoreactive neurons did not show TUNEL-labelled nuclei. Finally, all the type I neurons expressed the tyrosine hydroxylase mRNA at postnatal day 12, suggesting that the expression of the enzyme is a maturational step common to all these neurons and that the expression of the protein is not synchronized. Because the period of transient expression of tyrosine hydroxylase in type I neurons parallels the periods of maturation of evoked exocytosis in inner hair cells and of appearance and maturation of the cochlear potentials, we propose that the expression of the enzyme indicates the onset of hearing in individual type I primary auditory neurons. This enzyme expression could rely on a Ca2+ activation of its encoding gene subsequent to a sudden and massive Ca2+ entry through voltage-activated Ca2+ channels.

Animals↗
PubMed2002

Mutation analysis of 12 candidate genes for distal hereditary motor neuropathy type II (distal HMN II) linked to 12q24.3.

Distal hereditary motor neuropathies (distal HMNs) are characterized by degeneration of anterior horn cells of the spinal cord resulting in muscle weakness and atrophy. Distal HMN type II is genetically linked to chromosome 12q24.3 and located within a 13 cM region flanked by D12S86 and D12S340. We previously excluded 5 positional and functional candidate genes for distal HMN II. Here, we report the exclusion of 12 additional candidate genes localized within the distal HMN II region; the genes include musashi (Drosophila) homolog 1 (MSI1), protein inhibitor of neuronal nitric oxide synthase (PIN), peripherin (PRPH), tubulin alpha ubiquitous (K-ALPHA-1), tubulin alpha 3 (TUBA3), tubulin alpha 6 (TUBA6), splicing factor arginine/serine-rich 9 (SFRS9), U5 snRNP 100 kd (U5- 100K), putative chemokine receptor, GTP-binding protein (HM74), MondoA, cut (Drosophila)-like homeobox 2 (CUX2) and ADP-ribosylation factor 3 (ARF3).

Base Sequence↗
PubMed2001

Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of 18 cases.

Extraskeletal myxoid chondrosarcoma (EMCS) is an uncommon clinicopathologically well-defined tumor, but its pathogenesis and biologic behavior are poorly understood. We reviewed 18 cases of EMCS to verify clinicopathologic features and immunohistochemical profiles together with molecular detection of the tumor-specific fusion genes. The tumors were located mainly in the proximal extremities and limb girdles (72%). Two tumors arose at unusual anatomic sites: the finger and the hip joint. Nine of the 17 followed-up patients were alive and disease free, 4 were alive with recurrences and/or metastases, and 4 died of the tumor. Fifteen tumors showed typical features of EMCS, and 3 had hypercellular areas in addition to conventional EMCS areas. The tumors were variably immunoreactive for S-100 protein (50%), NSE (89%), peripherin (60%), and synaptophysin (22%). Chromogranin A and some epithelial markers (AE1/AE3, CAM5.2, and epithelial membrane antigen) were entirely negative. Frequent expressions of the neural/neuroendocrine markers suggest possible neural/neuroendocrine differentiation in at least some EMCSs, in addition to chondroid differentiation. In a reverse-transcription polymerase chain reaction (RT-PCR) assay using paraffin-embedded specimens, EWS-CHN or TAF2N-CHN fusion gene transcripts characteristic of EMCS could be detected in 15 (83%) of the 18 cases: EWS-CHN type 1 in 11 cases, EWS-CHN type 2 in 1, and TAF2N-CHN in 3. Three fusion-negative cases included 2 conventional EMCSs and 1 considered a "cellular" variant of the tumor. None of 30 other soft tissue and bone tumors with myxoid or chondroid morphology that we examined contained these fusion genes. Thus, RT-PCR detection of EWS-CHN or TAF2N-CHN fusion gene using archival paraffin-embedded tissue is a feasible and useful ancillary technique for the diagnosis of EMCS.

Adult↗
PubMed1995

Lineage specification of neuronal precursors in the mouse spinal cord.

We have investigated the differentiation potential of precursor cells within the developing spinal cord of mice and have shown that spinal cord cells from embryonic day 10 specifically give rise to neurons when plated onto an astrocytic monolayer, Ast-1. These neurons had the morphology of motor neurons and > 83% expressed the motor neuron markers choline acetyltransferase, peripherin, calcitonin gene-related peptide, and L-14. By comparison, < 10% of the neurons arising on monolayers of other neural cell lines or 3T3 fibroblasts had motor neuron characteristics. Cells derived from dorsal, intermediate, and ventral regions of the spinal cord all behaved similarly and gave rise to motor neuron-like cells when plated onto Ast-1. By using cells that expressed the lacZ reporter gene, it was shown that > 93% of cells present on the Ast-1 monolayers were motor neuron-like. Time-lapse analysis revealed that the precursors on the Ast-1 monolayers gave rise to neurons either directly or following a single cell division. Together, these results indicate that precursors in the murine spinal cord can be induced to differentiate into the motor neuron phenotype by factors produced by Ast-1 cells, suggesting that a similar factor(s) produced by cells akin to Ast-1 may regulate motor neuron differentiation in vivo.

Animals↗
PubMed1996

Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

Mutations in the human Cu,Zn superoxide dismutase gene (SOD1) are found in 20% of kindreds with familial amyotrophic lateral sclerosis. Transgenic mice (line G1H) expressing a human SOD1 containing a mutation of Gly-93 --> Ala (G93A) develop a motor neuron disease similar to familial amyotrophic lateral sclerosis, but transgenic mice (line N1029) expressing a wild-type human SOD1 transgene do not. Because neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of amyotrophic lateral sclerosis, we asked whether mutant G1H and/or N1029 mice develop similar NF lesions. NF inclusions (i.e., spheroids, Lewy body-like inclusions) were first detected in spinal cord motor neurons of the G1H mice at 82 days of age about the time these mice first showed clinical evidence of disease. Other neuronal intermediate filament proteins (alpha-internexin, peripherin) also accumulated in these spheroids. The onset of accumulations of ubiquitin immunoreactivity in the G1H mice paralleled the emergence of vacuoles and NF-rich spheroids in neurons, but they did not colocalize exclusively with spheroids. In contrast, NF inclusions were not seen in the N1029 mice until they were 132 days old, and ubiquitin immunoreactivity was not increased in the N1029 mice even at 199 days of age. Astrocytosis in spinal cord was associated with a marked increase in glial fibrillary acidic protein immunoreactivity in the G1H mice, but not in the N1029 mice. Finally, comparative studies revealed a striking similarity between the cytoskeletal pathology in the G1H transgenic mice and in patients with amyotrophic lateral sclerosis. These findings link a specific SOD1 mutation with alterations in the neuronal cytoskeleton of patients with amyotrophic lateral sclerosis. Thus, neuronal cytoskeletal abnormalities may be implicated in the pathogenesis of human familial amyotrophic lateral sclerosis.

Aging↗
PubMed1995

Peripheral nervous system-specific genes identified by subtractive cDNA cloning.

An improved method for constructing and screening subtractive cDNA libraries has been used to identify 46 mRNA transcripts that are expressed selectively in neonatal rat dorsal root ganglia (DRG) as judged by Northern blots and in situ hybridization. Sequence analysis demonstrates that both known (e.g. peripherin, calcitonin gene-related peptide, myelin P0) and novel identifiable transcripts (e.g. C-protein-like, synuclein-like, villin-like) are present in the library. Half of the transcripts (23) are undetectable in liver, kidney, heart, spleen, cerebellum, and cerebral cortex. Of the DRG-specific transcripts, 12 contain putative open reading frames that show no identity with known proteins. The construction of such a subtractive library thus provides us with both known and novel markers, and identifies new predicted DRG-specific proteins. In addition, the DRG-specific clones provide probes to define the regulatory elements that specify peripheral nervous-system-specific gene expression.

Amino Acid Sequence↗
PubMed2005

Glutamic acid-rich proteins of rod photoreceptors are natively unfolded.

The outer segment of vertebrate photoreceptors is a specialized compartment that hosts all the signaling components required for visual transduction. Specific to rod photoreceptors is an unusual set of three glutamic acid-rich proteins (GARPs) as follows: two soluble forms, GARP1 and GARP2, and the N-terminal cytoplasmic domain (GARP' part) of the B1 subunit of the cyclic GMP-gated channel. GARPs have been shown to interact with proteins at the rim of the disc membrane. Here we characterized native GARP1 and GARP2 purified from bovine rod photoreceptors. Amino acid sequence analysis of GARPs revealed structural features typical of "natively unfolded" proteins. By using biophysical techniques, including size-exclusion chromatography, dynamic light scattering, NMR spectroscopy, and circular dichroism, we showed that GARPs indeed exhibit a large degree of intrinsic disorder. Analytical ultracentrifugation and chemical cross-linking showed that GARPs exist in a monomer/multimer equilibrium. The results suggested that the function of GARP proteins is linked to their structural disorder. They may provide flexible spacers or linkers tethering the cyclic GMP-gated channel in the plasma membrane to peripherin at the disc rim to produce a stack of rings of these protein complexes along the long axis of the outer segment. GARP proteins could then provide the environment needed for protein interactions in the rim region of discs.

Amino Acid Sequence↗
PubMed2006

Voltage-gated sodium channels confer excitability to human odontoblasts: possible role in tooth pain transmission.

Odontoblasts are responsible for the dentin formation. They are suspected to play a role in tooth pain transmission as sensor cells because of their close relationship with nerve, but this role has never been evidenced. We demonstrate here that human odontoblasts in vitro produce voltage-gated tetrodotoxin-sensitive Na(+) currents in response to depolarization under voltage clamp conditions and are able to generate action potentials. Odontoblasts express neuronal isoforms of alpha2 and beta2 subunits of sodium channels. Co-cultures of odontoblasts with trigeminal neurons indicate a clustering of alpha2 and beta2 sodium channel subunits and, at the sites of cell-cell contact, a co-localization of odontoblasts beta2 subunits with peripherin. In vivo, sodium channels are expressed in odontoblasts. Ankyrin(G) and beta2 co-localize, suggesting a link for signal transduction between axons and odontoblasts. Evidence for excitable properties of odontoblasts and clustering of key molecules at the site of odontoblast-nerve contact strongly suggest that odontoblasts may operate as sensor cells that initiate tooth pain transmission.

Animals↗
PubMedDate not supplied

Pheochromocytomas and ganglioneuromas in the aging rats: morphological and immunohistochemical characterization.

We investigated, morphologically and immunohistochemically, 74 medullary adrenal tumors, including 64 pheochromocytomas (14 malignant and 50 benign), 9 ganglioneuromas, and 1 malignant schwannoma. The tumors were detected in 2-year-old Wistar and Sprague-Dawley rats from carcinogenicity studies. Morphologically, benign pheochromocytomas were characterized by monomorphic, small, basophilic cells with almost absence of mitoses. Malignant pheochromocytomas presented a low grade of pleomorphism, higher rate of mitoses, necrosis, infiltrative growth and in 1 case metastases in the lung. Ganglioneuromas were characterized by ganglion and neuron-like cells embedded in an eosinophilic matrix containing neurites, Schwann cells, and scant fibrovascular elements. All pheochromocytomas were strongly immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Subpopulations of chromaffin cells expressed chromogranin A (CGA) positivity. Matrix and Schwann cells were positive for S-100 and for glial fibrillary acidic protein (GFAP). In focal areas of the tumors, ganglion cells and axons were positive for neurofilament proteins (NFP) and synaptophysin. Ganglion cells exhibited peripherin and beta-tubulin. Proliferative activity of the tumors was assessed by immunostaining the endogenous cell proliferation associated-antigen Ki-67 and the proliferating cell nuclear antigen (PCNA). As expected, cell proliferation indices were much higher in malignant pheochromocytomas than in benign, yet ganglioneuromas remained immunonegative. Considering that Ki-67 antigen is more specific for cell proliferation, it should be regarded as marker of choice for supporting the differential diagnosis between benign and malignant pheochromocytomas.

Adrenal Gland Neoplasms↗
PubMed1987

Differences in the protein composition of bovine retinal rod outer segment disk and plasma membranes isolated by a ricin-gold-dextran density perturbation method.

The plasma membrane and disk membranes of bovine retinal rod outer segments (ROS) have been purified by a novel density-gradient perturbation method for analysis of their protein compositions. Purified ROS were treated with neuraminidase to expose galactose residues on plasma membrane-specific glycoproteins and labeled with ricin-gold-dextran particles. After the ROS were lysed in hypotonic buffer, the plasma membrane was dissociated from the disks by either mild trypsin digestion or prolonged exposure to low ionic strength buffer. The dense ricin-gold-dextran-labeled plasma membrane was separated from disks by sucrose gradient centrifugation. Electron microscopy was used to follow this fractionation procedure. The dense red pellet primarily consisted of inverted plasma membrane vesicles containing gold particles; the membrane fraction of density 1.13 g/cc consisted of unlabeled intact disks and vesicles. Ricin-binding studies indicated that the plasma membrane from trypsin-treated ROS was purified between 10-15-fold. The protein composition of plasma membranes and disks was significantly different as analyzed by SDS gels and Western blots labeled with lectins and monoclonal antibodies. ROS plasma membrane exhibited three major proteins of 36 (rhodopsin), 38, and 52 kD, three ricin-binding glycoproteins of 230, 160, and 110 kD, and numerous minor proteins in the range of 14-270 kD. In disk membranes rhodopsin appeared as the only major protein. A 220-kD concanavalin A-binding glycoprotein and peripherin, a rim-specific protein, were also present along with minor proteins of 43 and 57-63 kD. Radioimmune assays indicated that the ROS plasma membrane contained about half as much rhodopsin as disk membranes.

Animals↗
PubMed1995

An eighth locus for autosomal dominant retinitis pigmentosa is linked to chromosome 17q.

Retinitis pigmentosa is one of the most common causes of severe visual handicap in middle to late life. Prior to this report, seven loci had previously been mapped for the autosomal dominant form of this disorder (adRP). We now report the identification of a novel adRP locus on chromosome 17q. To map the new locus, we performed linkage analysis with microsatellite markers in a large South African kindred. After exclusion of 13 RP candidate gene loci (including rhodopsin and peripherin-RDS), we obtained significant positive lod scores at zero recombination fraction (theta = 0) for D17S808 (Z = 4.63) and D17S807 (Z = 5.69). Multipoint analysis gave a maximum lod score of 8.28 between these two markers. From haplotype analysis, the disease locus lies in the interval between markers D17S809 and D17S942. Three candidate genes for retinal dystrophies map to this chromosomal region and these genes are currently being investigated for possible involvement with adRP in this family.

Adult↗
PubMed1998

Desmoplastic small round cell tumor: II: an ultrastructural and immunohistochemical study with emphasis on new immunohistochemical markers.

In order to investigate the histogenesis and facilitate the diagnosis of desmoplastic small round cell tumor (DSRCT), 39 cases were studied by immunohistochemical methods using a large battery of antibodies directed against a wide variety of epithelial, mesenchymal, and neural-associated proteins. Sixteen of these tumors were also studied by electron microscopy. Thirty-seven of 39 cases reacted for cytokeratin using a "cocktail" of 3 monoclonal antibodies (CAM 5.2/AE1/AE3), 39/39 for desmin, 24/25 for epithelial membrane antigen, 22/27 for vimentin, 18/25 for neuron-specific enolase, 10/15 for CD57 (Leu-7), 3/19 for synaptophysin, 1/22 for chromogranin, 3/19 for muscle-specific actin, 3/16 for alpha-smooth-muscle actin, 11/16 for CD15 (Leu-M1), 5/12 for CA-125, 6/17 for CD99, 9/10 for MOC-31, 2/6 for NB84, 5/7 for Ber-EP4, and 8/9 for the Wilms tumor (WT1) protein. No staining was obtained in any of the cases tested for cytokeratin 5/6 or 20, neurofilament proteins, glial fibrillary acidic protein, peripherin, CA19-9, thrombomodulin, alphafetoprotein, carcinoembryonic antigen, TAG-72 (B72.3), placental alkaline phosphatase, S-100 protein, HMB-45, myoglobin, or for the two myogenic regulatory proteins myogenin and MyoD1. A frequent ultrastructural finding was the presence of juxtanuclear aggregates of intermediate filaments, but microfilaments with densities or Z-band-like material suggestive of either smooth or skeletal muscle differentiation were not seen in any case. Dendritic-like processes containing microtubules and dense core granules were seen in four tumors and all of these tumors reacted for at least one of the neural markers investigated. Although ultrastructural and immunohistochemical studies confirmed previous observations that DSRCTs present epithelial, mesenchymal, and neural phenotypes, a great variation was found in the frequency of expression of the different markers used to demonstrate each line of cell differentiation. The absence of expression of cytokeratin 5/6 and thrombomodulin together with positive staining for CD15, MOC-31, and Ber-EP4 argues against the possible mesothelial origin that has been suggested for this tumor. Additionally since none of the tumors reacted for myogenin or MyoD1, desmin expression in DSRCT cannot be regarded as evidence of skeletal muscle differentiation. Although the histogenesis of DSRCT remains unknown, it is believed that this tumor originates from a progenitor cell with potential for multiphenotypic differentiation.

Abdominal Neoplasms↗
PubMed2001

Immunohistochemical detection of Schwann cells in innervated and vascularized human intervertebral discs.

STUDY DESIGN: The ingrowth of nerves, blood vessels, and Schwann cells into human intervertebral discs was examined using immunohistochemistry for cell-type-specific markers. OBJECTIVES: To determine whether Schwann cells may contribute to disc innervation, and to assess the relation between disc innervation and vascularization. SUMMARY OF BACKGROUND DATA: Intervertebral disc degeneration was associated previously with ingrowth of blood vessels and nerves. Schwann cells are known to play an important role in regulating nerve growth and survival in other tissues, but they have not been examined in human pathologic intervertebral discs. METHODS: Serial sections of human intervertebral discs were immunostained for the neuronal markers (neurofilament 200, peripherin, protein gene product 9.5), for the Schwann cell marker (glial fibrillary acidic protein), and for the endothelial cell marker (CD34). RESULTS: Glial fibrillary acidic protein-immunopositive cells colocalized with nerves in degenerate discs, but were absent or rarely observed in nondegenerate, aneural discs. These also were seen in the disc matrix, independently of nerves. Much of the nerve and Schwann cell ingrowth was found in vascularized areas of disc tissue, where the lamellar structure of the anulus fibrosus was disrupted. Blood vessels were observed deeper into the discs than nerves or Schwann cells. CONCLUSIONS: The appearance of glial fibrillary acidic protein-immunopositive cells in diseased intervertebral discs was closely associated with nerve ingrowth. This novel finding suggests that Schwann cells have a role to play in regulating disc innervation and nerve function in the disc. Because blood vessels were observed furthermost into the disc, it is possible that degenerate disc vascularization occurs before innervation.

Adolescent↗
PubMed2000

Recent advances in amyotrophic lateral sclerosis.

The mechanisms by which mutations of the SOD1 gene cause selective motor neuron death remain uncertain, although interest continues to focus on the role of peroxynitrite, altered peroxidase activity of mutant SOD1, changes in intracellular copper homeostasis, protein aggregation, and changes in the function of glutamate transporters leading to excitotoxicity. Neurofilaments and peripherin appear to play some part in motor neuron degeneration, and amyotrophic lateral sclerosis is occasionally associated with mutations of the neurofilament heavy chain gene. Linkage to several chromosomal loci has been established for other forms of familial amyotrophic lateral sclerosis, but no new genes have been identified. In the clinical field, interest has been shown in the population incidence and prevalence of amyotrophic lateral sclerosis and the clinical variants that cause diagnostic confusion. Transcranial magnetic stimulation has been used to detect upper motor neuron damage and to explore cortical excitability in amyotrophic lateral sclerosis, and magnetic resonance imaging including proton magnetic resonance spectroscopy and diffusion weighted imaging also provide useful information on the upper motor neuron lesion. Aspects of care including assisted ventilation, nutrition, and patient autonomy are addressed, and underlying these themes is the requirement to measure quality of life with a new disease-specific instrument. Progress has been made in developing practice parameters. Riluzole remains the only drug to slow disease progression, although interventions such as non-invasive ventilation and gastrostomy also extend survival.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Microarray analysis in the HSV-1 latently infected mouse trigeminal ganglion.

PURPOSE: To review our previous studies regarding alterations in gene expression in HSV-1 latently infected mouse trigeminal ganglia (TGs) following treatment with immunosuppressants and hyperthermia. METHODS: Uninfected and HSV-1 latently infected mice were treated with immunosuppressants or heat stressed (43 degrees C for 10 minutes). In the immunosuppressant study, 4 groups of animals were examined: (1) uninfected, not treated; (2) uninfected, drug-treated; (3) latently infected, not treated; and (4) latently infected, drug-treated. In the hyperthermia study, TG from 6 groups of mice were studied: (1) uninfected, not stressed; (2) uninfected, heat-stressed; killed at 6 hours after hyperthermia; (3) uninfected, heat-stressed, killed at 24 hours after hyperthermia; (4) latently infected, not stressed; (5) latently infected, heat-stressed, killed at 6 hours after hyperthermia; and (6) latently infected, heat-stressed, killed at 24 hours after hyperthermia. PolyA mRNA from the TGs of each group was reverse-transcribed, labeled with P, incubated on a gene array membrane, and analyzed by phosphorimaging. As a comparison and to confirm microarray results, semiquantitative RT-PCR for selected genes was also performed. RESULTS: The immunosuppressive drugs significantly increased expression of two genes--calpactin 1 light chain and guanine nucleotide-binding protein alpha stimulating activity polypeptide (GNAS)--in the ganglia of uninfected mice compared with untreated, uninfected mice. Ten genes were shown to be significantly increased in the latent TGs from mice treated with the immunosuppressants compared with latently infected untreated mice. These genes were prostaglandin E2 receptor EP4 subtype (PTGER4), insulin promoter factor 1 (IPF1), glutathione S-transferase mu2, cyclin D2, peripherin, plasma glutathione peroxidase, methyl CpG-binding protein 2, retinal S-antigen, ErbB2 protooncogene, and GNAS. Eight genes were shown to be significantly decreased in the HSV-1 latent TGs treated with the drugs compared with untreated latent mice. These genes were peripheral myelin protein 22, decorin, transcription factor AP-1, dystroglycan 1, myelin protein zero, mitogen-activated protein kinase 3, prothymosin beta4, and brain lipid-binding protein. The results obtained by semiquantitative RT-PCR results were similar to those obtained by microarray analysis. Six hours after heat stress, the genes whose expression was altered included the FK506-binding protein gene (decreased), the T-complex protein 1alpha subunit gene (increased), and the 94-kDa glucose-regulated protein gene (increased in uninfected TG, decreased in infected TG). Heat stress increased expression of the DNA excision repair protein ERCC5 gene 24 hours after the treatment. Genes previously reported to exhibit increased transcription 1 hour after heat stress did not continue to show significant transcriptional activation at 6 or 24 hours. CONCLUSIONS: Those genes whose expression is altered by immunosuppressive drug treatment may play an important role in ocular HSV-1 recurrence. Changes in gene expression in the prostaglandin pathway, a transcription factor, and an enzyme in the cell cycle are considered of special importance for HSV-1 reactivation by immunosuppression. Altered gene expression at 6 and 24 hours after heat stress was different from previously reported changes in gene expression 1 hour after hyperthermia in HSV-1 latently infected mice.

Animals↗
PubMed2005

The pathobiology of amyotrophic lateral sclerosis: a proteinopathy?

Amyotrophic lateral sclerosis (ALS) is increasingly considered to be a disorder of multiple etiologies that have in common progressive degeneration of both upper and lower motor neurons, ultimately giving rise to a relentless loss of muscle function. This progressive degeneration is associated with heightened levels of oxidative injury, excitotoxicity, and mitochondrial dysfunction--all occurring concurrently. In this article, we review the evidence that suggests, in common with other age-dependent neurodegenerative disorders, that ALS can be considered a disorder of protein aggregation. Morphologically, this is evident as Bunina bodies, ubiquitin-immunoreactive fibrils or aggregates, neurofilamentous aggregates, mutant copper/zinc superoxide dismutase (SOD1) aggregates in familial ALS variants harboring mutations in SOD1, peripherin-immunoreactive aggregates within spinal motor neurons and as neuroaxonal spheroids, and in an increasingly greater population of patients with ALS with cognitive impairment, both intra- and extraneuronal tau aggregates. We review the evidence that somatotopically specific patterns of altered kinase and phosphatase activity are associated with alterations in the phosphorylation state of these proteins, altering either solubility or assembly characteristics. The role of nonneuronal cells in mediating motor neuronal injury is discussed in the context of alterations in tyrosine kinase activity and enhanced protein phosphorylation.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Merkel cells in mouse skin: intermediate filament pattern, localization, and hair cycle-dependent density.

The distribution and antigen expression of Merkel cells in mouse skin is as yet ill defined. Since the mouse offers an excellent model for studying the origin and functions of Merkel cells, the Merkel cell distribution as well as the expression of intermediate filament proteins and neuronal markers was characterized in C57 BL/6 mouse skin by immunohistochemistry and electron microscopy. Merkel cells in whisker pads, back, and foot pad skin as identified by staining for neuron-specific enolase-an established neuroendocrine marker--expressed cytokeratins (CK) 8,18, and 20 (i.e., simple-epithelial CKs), but not CKs 4 and 13. Sequential double staining for neuron-specific enolase and CK 20 showed consistent co-expression in Merkel cells, establishing CK 20 as a specific immunocytochemical marker for mouse Merkel cells. The Merkel cells also were immunoreactive for synaptophysin but not for neurofilament proteins, peripherin, S-100 protein, and neural cell adhesion molecule. Using CK 8, 18, and 20 as markers, we detected many Merkel cells in the outer roots sheath of vibrissae hair follicles and in foot pad skin. However, only few Merkel cells were found in back skin. These were restricted to small clusters, localized basally within the Haarscheiben epidermis of tylotrich hair follicles, and formed close contacts to prominent nerve fiber terminals as shown by electron microscopy. In striking contrast to human skin, Merkel cells were never found in the epithelium of pelage hair follicles. Even more strikingly, the density of Haarscheiben-associated Merkel cells changed substantially during the highly synchronized, depilation-induced C 57 BL/6 hair cycle, with a minimum in back skin with all hair follicles in telogen or catagen, and a maximum in back skin with all hair follicles in anagen IV-VI. These observations on the Merkel cell hair cycle-dependent distribution in murine skin point to important differences in Merkel cell functions between humans and mice, and raise intriguing questions as to the role of Merkel cells in hair biology.

Animals↗