Lens Biology is a Dimension of Neurobiology.

There is a second cell type in your body that expresses scores of the most intensively studied genes in neuroscience and exclusively shares critical interdependent modes of molecular regulation that include a network first described as responsible for the basic bifurcation of neuronal from non-neuronal gene expression in vertebrates. Neurons and lens cells are among the most ancient animal cell types, yet neurons have an exclusive status also attributed to roles underlying sensation, movement, and cognition. However, this status is challenged by cells in the lens of the eye.

KCC2 expression supersedes NKCC1 in mature fiber cells in mouse and rabbit lenses.

Purpose: Na-K-Cl cotransporter 1 (NKCC1) and K-Cl cotransporter 2 (KCC2) have fundamental roles in neuron differentiation that are integrated with gamma-aminobutyric acid (GABA) and glutamate receptors, GABA synthesized by GAD25/65/67 encoded by GAD1/GAD2 genes, and GABA transporters (GATs). Cells in the eye lens express at least 13 GABA receptor subunits, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl D-aspartate (NMDA) glutamate receptors, GAD1/GAD2, GAT1-4 and vGAT, and NKCC1. NKCC1:KCC2 ratios determine the switch in GABA actions from trophic/growth promoting early in development to their classic inhibitory roles in adult neurons.

Fragile X Syndrome FMRP Co-localizes with Regulatory Targets PSD-95, GABA Receptors, CaMKIIα, and mGluR5 at Fiber Cell Membranes in the Eye Lens.

Fmr1 and FMRP underlie Fragile X Syndrome (FXS) and are linked with related autism spectrum disorders (ASD). Fmr1 also has an essential role in eye and lens development. Lenses express FMRP along with γ-aminobutyric acid (GABA) receptors (GABARs), post-synaptic density protein 95 (PSD-95), Tyr-phosphatase STEP, CaMKIIα and Alzheimer's disease Aβ precursor protein, which are verified targets of FMRP regulation in neurons and outline major topics in FXS/ASD research.

Lens GABA receptors are a target of GABA-related agonists that mitigate experimental myopia.

Coordinated growth of eye tissues is required to achieve visual acuity. However, visual experience also guides this process. Experimental myopia can be produced by altering light entering the eye, but also by changing light/dark regimens.

"Moonlighting" GAPDH Protein Localizes with AMPA Receptor GluA2 and L1 Axonal Cell Adhesion Molecule at Fiber Cell Borders in the Lens.

Purpose: The canonical role of glyceraldehyde phosphate dehydrogenase (GAPDH) is as an enzyme in glycolysis. GAPDH is also a principal "moonlighting" protein with additional roles at diverse sites in a variety of cells. Surface GAPDH on mammalian, yeast, and bacterial cells acts as a receptor and also mediates cell contacts.

PTBP-dependent PSD-95 and CamKIIα alternative splicing in the lens.

Purpose: Parallels described between neurons and lens fiber cells include detailed similarities in sub-cellular structures that increasingly show shared expression of genes involved in the construction and function of these structures in neurons. Intriguingly, associated modes of molecular regulation of these genes that had been thought to distinguish neurons have been identified in the lens as well. Both elongated cell types form membrane protrusions with similar size, shape, and spacing that exclude microtubules, contain F-actin, and are coated with the clathrin/AP-2 adaptor.

Expression and targeting of lymphocyte function-associated antigen 1 (LFA-1) on white blood cells for treatment of allergic asthma.

Allergic asthma is a chronic respiratory disease that results from an exaggerated inflammatory response in the airways. Environment stimuli, such as pollen and HDM, cause activation and migration of inflammatory WBCs into the respiratory tract, where they cause lung damage. Migration of these WBCs is dependent on the active configuration of the β2 integrin LFA-1.

NMDA glutamate receptor NR1, NR2A and NR2B expression and NR2B Tyr-1472 phosphorylation in the lens.

Detailed parallels described between lens fiber cell and neuron morphology, sub-cellular structure, and molecular biology include striking similarities in the ultrastructure of their vesicle transport machinery and the membrane protrusions that occur along the lateral surfaces of both cell types. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate receptor (NMDA) glutamate receptors (AMPARs/NMDARs) are the predominant receptors in neurons. These receptors have fundamental roles in neuron morphogenesis as well as neuron physiology and dynamic cell signaling, and specifically at dendritic spines.

Leukotoxin kills rodent WBC by targeting leukocyte function associated antigen 1.

Leukotoxin is a protein that is secreted by Aggregatibacter actinomycetemcomitans and that primarily targets the active form of leukocyte function associated antigen 1 (LFA1) on WBC. Because of its specificity for WBC, leukotoxin is being developed as a novel biologic treatment for hematologic malignancies and autoimmune-inflammatory diseases. Early studies indicated that leukotoxin is specific for WBC from humans and Old World primates.

Amyloid-β and tau pathology of Alzheimer's disease induced by diabetes in a rabbit animal model.

Alzheimer's disease (AD) is the major age-dependent disease of the brain, but what instigates late-onset AD is not yet clear. Epidemiological, animal model, and cell biology findings suggest links between AD and diabetes. Although AD pathology is accelerated by diabetes in mice engineered to accumulate human-sequence amyloid-β (Aβ) peptides, they do not adequately model non-inherited AD.

Novel Detox Gel Depot sequesters β-Amyloid Peptides in a mouse model of Alzheimer's Disease.

Alzheimer's Disease (AD), a debilitating neurodegenerative disease is caused by aggregation and accumulation of a 39-43 amino acid peptide (amyloid β or Aβ) in brain parenchyma and cerebrovasculature. The rational approach would be to use drugs that interfere with Aβ-Aβ interaction and disrupt polymerization. Peptide ligands capable of binding to the KLVFF (amino acids 16-20) region in the Aβ molecule have been investigated as possible drug candidates.

Parallels between neuron and lens fiber cell structure and molecular regulatory networks.

Studies over the past fifty years have identified extensive similarities between neurons and elongated fiber cells that make up in the interior of the ocular lens. Electron micrographs showed parallels in the organization of their intracellular vesicle transport machinery and between lens fiber cell lateral protrusions and dendritic spines. Consistent with those observations, a number of gene products first characterized as highly neuron-preferred in their expression were also demonstrated in lens fiber cells.

GluA2 AMPA glutamate receptor subunit exhibits codon 607 Q/R RNA editing in the lens.

Regulated GluA2 AMPA receptor subunit expression, RNA editing, and membrane localization are fundamental determinants of neuronal Ca(2+) influx, and underlie basic functions such as memory and the primary brain disorder epilepsy. Consistent with this, AMPARs, and specifically GluA2, are targets of common antiepileptic drugs (AEDs) and antidepressants. Recently, epidemiological associations between epilepsy and increased cataract prevalence were found comparable to cataract links with diabetes and smoking.

Probing the role of aromatic residues at the secondary saccharide-binding sites of human salivary alpha-amylase in substrate hydrolysis and bacterial binding.

Human salivary alpha-amylase (HSAmy) has three distinct functions relevant to oral health: (1) hydrolysis of starch, (2) binding to hydroxyapatite (HA), and (3) binding to bacteria (e.g., viridans streptococci).

Detoxification depot for beta-amyloid peptides.

Alzheimer's Disease (AD) is caused by the deposition of insoluble and toxic amyloid peptides (Abeta) in the brain leading to memory loss and other associated neurodegenerative symptoms. To date there is limited treatment options and strategies for treating AD. Studies have shown that clearance of the amyloid plaques from the brain and thus from the blood could be effective in stopping and or delaying the progression of the disease.

Tyrosine sulfation of statherin.

Tyrosylprotein sulfotransferase (TPST), responsible for the sulfation of a variety of secretory and membrane proteins, has been identified and characterized in submandibular salivary glands (William et al. Arch Biochem Biophys 1997; 338: 90-96). In the present study we demonstrate the sulfation of a salivary secretory protein, statherin, by the tyrosylprotein sulfotransferase present in human saliva.

Ethanol decreases rat hepatic arylsulfatase A activity levels.

Background: Arylsulfatase A (ASA) is an enzyme that catalyzes the degradation of sulfatides, a glycosphingolipid found in many tissues, but predominantly in myelin and kidney. Arylsulfatase A is 1 member of a family of sulfatases that is activated by a required co- or posttranslational modification with the oxidation of cysteine to formylglycine. This conversion requires a novel oxygenase mechanism that can be inhibited by reactive oxygen species.

An in vitro evaluation of the effect of sealant characteristics on laser fluorescence for caries detection.

Purpose: The purposes of this study were to: (1) evaluate the ability of a laser fluorescence (LF) unit to detect simulated caries under pit and fissure sealants; (2) determine the effect of an opacifying agent in sealants on LF values; and (3) determine interexaminer reproducibility values of the unit in a highly controlled, laboratory setting. Sealant characteristics specifically considered were: (1) filler content; (2) opacity; and (3) intrinsic fluorescence.

Methods: Three sealants were used in this study: 2 unfilled and 1 filled.

Tyrosine sulfation of arylsulfatase A and its peptide.

Purified human liver arylsulfatase A (ASA) as well as an ASA peptide (residues 28-39) were sulfated by tyrosyl protein sulfotransferase in vitro. The media, but not the cell lysate, of normal human fibroblasts contained a tyrosine sulfated protein (pI = 4.5-5.

Identification and characterization of tyrosylprotein sulfotransferase from human saliva.

Tyrosylprotein sulfotransferase (TPST), the enzyme responsible for the sulfation of tyrosine residues, has been identified and characterized in submandibular salivary glands previously (William et al. Arch Biochem Biophys 338: 90-96). Tyrosylprotein sulfotransferase catalyses the sulfation of a variety of secretory and membrane proteins and is believed to be present only in the cell.

The future of proteomics in the study of alcoholism.

This article represents the proceedings of a workshop at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The workshop organizers/chairpersons were Chinnaswamy Kasinathan and Paul Manowitz. The presentations were (1) Introduction to the field of proteomics, by Kent Vrana; (2) Use of proteomics in the identification of urinary biomarkers for alcohol intake, by Chinnaswamy Kasinathan, Paul Thomas, and Paul Manowitz; (3) Proteomics screening illuminates ethanol-mediated induction of HDL proteins in macaques, by Kent Vrana, Randy Gooch, Travis Worst, Stephen Walker, Aaron Xu, Peter Pierre, Heather Green, and Kathleen Grant; and (4) Proteomics applied to the study of the liver, by Laura Beretta.

In vivo induction of tyrosylprotein sulfotransferase by ethanol: role of increased enzyme synthesis.

Tyrosine sulfation is a posttranslational modification involved in the synthesis, secretion, and biological activity of proteins and peptides. Our previous studies have demonstrated that the enzyme activity was induced by ethanol. In the present work, the induction was studied in detail.

Stimulation of tyrosylprotein sulfotransferase activity by ethanol: role of increased enzyme level.

Tyrosylprotein sulfotransferase (TPST), an enzyme involved in the posttranslational modification of proteins, plays important role in the biological activity and secretion of proteins. Previously we have shown an increased activity of this enzyme in gastric mucosa of alcoholics. In the present study, effect of ethanol on TPST was examined in rat liver and gastric mucosa utilizing enzyme assays and Western blot analyses for TPST levels.

Isolation of tyrosylprotein sulfotransferase from rat liver.

1. Tyrosylprotein sulfotransferase (TPST) is involved in the posttranslational modification of proteins and plays a critical role in the biological activity and secretion of proteins. A simple method has been developed to isolate the TPST (28% yield) from rat liver, using polyclonal anti-TPST antibodies.

Purification of tyrosylprotein sulfotransferase from rat submandibular salivary glands.

Tyrosylprotein sulfotransferase (TPST), the enzyme responsible for the sulfation of tyrosine residues, has been identified and characterized in submandibular salivary glands. In the present study, this enzyme was purified from the Golgi membranes of rat submandibular salivary glands using a Cibacron blue F3GA affinity column chromatography. Antibodies raised in rabbit against TPST detected the purified enzyme (50-54 kDa) and proteins consisting of molecular mass 50-54 kDa in the Golgi membranes of liver, submandibular salivary glands, stomach, cerebellum, thalamus, and pituitary.