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Featured researches published by Tamao Endo.


Biochemical and Biophysical Research Communications | 2003

Loss-of-function of an N-acetylglucosaminyltransferase, POMGnT1, in muscle-eye-brain disease.

Hiroshi Manya; Keiwa Sakai; Kazuhiro Kobayashi; Kiyomi Taniguchi; Masao Kawakita; Tatsushi Toda; Tamao Endo

Muscle-eye-brain disease (MEB), an autosomal recessive disorder, is characterized by congenital muscular dystrophy, brain malformation, and ocular abnormalities. Previously, we found that MEB is caused by mutations in the gene encoding the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1), which is responsible for the formation of the GlcNAcbeta1-2Man linkage of O-mannosyl glycan. Although 13 mutations have been identified in patients with MEB, only the protein with the most frequently observed splicing site mutation has been studied. This protein was found to have no activity. Here, we expressed the remaining mutant POMGnT1s and found that none of them had any activity. These results clearly demonstrate that MEB is inherited as a loss-of-function of POMGnT1.


Journal of Biological Chemistry | 2004

The twisted abdomen phenotype of Drosophila POMT1 and POMT2 mutants coincides with their heterophilic protein O-mannosyltransferase activity.

Tomomi Ichimiya; Hiroshi Manya; Yoshiko Ohmae; Hideki Yoshida; Kuniaki Takahashi; Ryu Ueda; Tamao Endo; Shoko Nishihara

Walker-Warburg syndrome, caused by mutations in protein O-mannosyltransferase-1 (POMT1), is an autosomal recessive disorder characterized by severe brain malformation, muscular dystrophy, and structural eye abnormalities. As humans have a second POMT, POMT2, we cloned each Drosophila ortholog of the human POMT genes and carried out RNA interference (RNAi) knock-down to investigate the function of these proteins in vivo. Drosophila POMT2 (dPOMT2) RNAi mutant flies showed a “twisted abdomen phenotype,” in which the abdomen is twisted 30–60°, similar to the dPOMT1 mutant. Moreover, dPOMT2 interacted genetically with dPOMT1, suggesting that the dPOMTs function in collaboration with each other in vivo. We expressed dPOMTs in Sf21 cells and measured POMT activity. dPOMT2 transferred a mannose to the dystroglycan protein only when it was coexpressed with dPOMT1. Likewise, dPOMT1 showed POMT activity only when coexpressed with dPOMT2, and neither dPOMT showed any activity by itself. Each dPOMT RNAi fly totally reduced POMT activity, despite the specific reduction in the level of each dPOMT mRNA. The expression pattern of dPOMT2 mRNA was found to be similar to that of dPOMT1 mRNA using whole mount in situ hybridization. These results demonstrate that the two dPOMTs function as a protein O-mannosyltransferase in association with each other, in vitro and in vivo, to generate and maintain normal muscle development.


Journal of Biological Chemistry | 2006

Physical and functional association of human protein o-mannosyltransferases 1 and 2

Keiko Akasaka-Manya; Hiroshi Manya; Ai Nakajima; Masao Kawakita; Tamao Endo

A defect of protein O-mannosylation causes congenital muscular dystrophy with brain malformation and structural eye abnormalities, so-called Walker-Warburg syndrome. Protein O-mannosylation is catalyzed by protein O-mannosyltransferase 1 (POMT1) and its homologue, POMT2. Coexpression of POMT1 and POMT2 is required to show O-mannosylation activity. Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo. Recently, three mutations were reported in the POMT1 gene of patients who showed milder phenotypes than typical Walker-Warburg syndrome. We coexpressed these mutant POMT1s with POMT2 and found that none of them had any activity. However, all POMT1 mutants, including previously identified POMT1 mutants, coprecipitated with POMT2. These results indicate that the mutant POMT1s could form heterocomplexes with POMT2 but that such complexes are insufficient for enzymatic activity.


Glycoconjugate Journal | 2004

Structure, function and pathology of O-mannosyl glycans.

Tamao Endo

Animal cells contain many glycoproteins, i.e., proteins with covalently liked sugar chains. The major glycans of glycoproteins can be classified into two groups, N-glycans and O-glycans, according to their glycan-peptide linkage regions. Development of sensitive methods for the analyses of glycan structures have revealed a new type of glycosidic linkage to the peptide portion, the O-mannosyl linkage, in mammals, which used to be considered specific to yeast. O-Mannosylation is present in a limited number of glycoproteins of brain, nerve, and skeletal muscle. Recently O-mannosylation has been shown to be important in muscle and brain development. Glycobiology of O-mannosyl glycans is expected to produce remarkable advances in the understanding and treatment of congenital muscular dystrophies. In this article, I describe the structure, biosynthesis, and pathology of O-mannosyl glycans. Published in 2004.


Journal of Neurochemistry | 2006

Sialylation enhances the secretion of neurotoxic amyloid-β peptides

Kazuhiro Nakagawa; Shinobu Kitazume; Ritsuko Oka; Kei Maruyama; Takaomi C. Saido; Yuji Sato; Tamao Endo; Yasuhiro Hashimoto

Alzheimers disease (AD) is characterized by amyloid‐β peptide (Aβ) deposition in the brain. Aβ is produced by sequential cleavage of amyloid precursor protein (APP) by β‐secretase (BACE1: β‐site APP‐cleaving enzyme 1) and γ‐secretase. Previously, we demonstrated that BACE1 also cleaves β‐galactoside α2,6‐sialyltransferase (ST6Gal‐I) and down‐regulates its transferase activity. Here, we report that overexpression of ST6Gal‐I in Neuro2a cells enhanced α2,6‐sialylation of endogenous APP and increased the extracellular levels of its metabolites [Aβ by two‐fold, soluble APPβ (sAPPβ) by three‐fold and sAPPα by 2.5‐fold). Sialylation‐deficient mutant (Lec‐2) cells secreted half as much Aβ as wild‐type Chinese hamster ovary (CHO) cells. Furthermore, wild‐type CHO cells showed enhanced secretion of the APP metabolites upon ST6Gal‐I overexpression, whereas Lec‐2 cells did not, indicating that the secretion enhancement requires sialylation of cellular protein(s). Secretion of metabolites from a mutant APP (APP‐Asn467,496Ala) that lacked N‐glycosylation sites was not enhanced upon ST6Gal‐I overexpression, suggesting that the N‐glycans on APP itself are required for the enhanced secretion. In the mouse brain, the amount of α2,6‐sialylated APP appeared to be correlated with the sAPPβ level. These results suggest that sialylation of APP promotes its metabolic turnover and could affect the pathology of AD.


Congenital Anomalies | 2003

Fukuyama-type congenital muscular dystrophy (FCMD) and α-dystroglycanopathy

Tatsushi Toda; Kazuhiro Kobayashi; Satoshi Takeda; Junko Sasaki; Hiroki Kurahashi; Hiroki Kano; Masaji Tachikawa; Fan Wang; Yoshitaka Nagai; Kiyomi Taniguchi; Mariko Taniguchi; Yoshihide Sunada; Toshio Terashima; Tamao Endo; Kiichiro Matsumura

ABSTRACT  Fukuyama‐type congenital muscular dystrophy (FCMD), Walker‐Warburg syndrome (WWS), and muscle‐eye‐brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. Through positional cloning, we identified the gene for FCMD and MEB, which encodes the fukutin protein and the protein O‐linked mannose β1, 2‐N‐acetylgIucosaminy ltransferase (POMGnT1), respectively. Recent studies have revealed that posttranslational modification of α‐dystro‐glycan is associated with these congenital muscular dystrophies with brain malformations. In this review Fukuyama‐type congenital muscular dystrophy (FCMD), other CMDs with brain malformations, and their relation with α‐dystroglycan are discussed.


FEBS Letters | 2005

Aberrant glycosylation of α‐dystroglycan causes defective binding of laminin in the muscle of chicken muscular dystrophy

Fumiaki Saito; Martina Blank; Jörn E. Schröder; Hiroshi Manya; Teruo Shimizu; Kevin P. Campbell; Tamao Endo; Makoto Mizutani; Stephan Kröger; Kiichiro Matsumura

Dystroglycan is a central component of dystrophin–glycoprotein complex that links extracellular matrix and cytoskeleton in skeletal muscle. Although dystrophic chicken is well established as an animal model of human muscular dystrophy, the pathomechanism leading to muscular degeneration remains unknown. We show here that glycosylation and laminin‐binding activity of α‐dystroglycan (α‐DG) are defective in dystrophic chicken. Extensive glycan structural analysis reveals that Galβ1‐3GalNAc and GalNAc residues are increased while Siaα2‐3Gal structure is reduced in α‐DG of dystrophic chicken. These results implicate aberrant glycosylation of α‐DG in the pathogenesis of muscular degeneration in this model animal of muscular dystrophy.


Neuroscience Letters | 2005

Comparison of hippocampal synaptosome proteins in young-adult and aged rats

Yuji Sato; Hidenori Yamanaka; Tosifusa Toda; Yasuro Shinohara; Tamao Endo

The hippocampus is important in learning and memory functions but its ability to aid in these functions declines during aging. In this study, we examined hippocampal proteins whose expressions changed in the aging process. A comparison of synaptosome proteins of hippocampus prepared from young-adult (9-week-old) rats with those from aged (30-month-old) rats by two-dimensional fluorescence difference gel electrophoresis revealed 24 spots that were expressed differently among about 1000 spots detected in both young-adult and aged rat samples. Nineteen of these 24 spots were identified by peptide mass fingerprinting. These proteins included chaperone proteins and proteins related to the cytoskeleton, neurotransmission, signal transduction and energy supply. The cytoskeleton-related proteins included actin and T-complex 1, which is thought to play a role in actin folding. Actin was up-regulated but T-complex 1 was down-regulated in aged rat synapses. These results suggest that age-dependent changes of actin filament formation are related to neuronal dysfunction associated with aging.


Mechanisms of Ageing and Development | 2006

Identification and characterization of an increased glycoprotein in aging: age-associated translocation of cathepsin D.

Yuji Sato; Yusuke Suzuki; Emi Ito; Sayaka Shimazaki; Masami Ishida; Takaki Yamamoto; Haruhiko Yamamoto; Tosifusa Toda; Minoru Suzuki; Akemi Suzuki; Tamao Endo

We found that 14 N-glycosylated proteins were accumulated in the rat cerebral cortex cytosolic fraction in the aging process by a comparative study with two-dimensional gel electrophoresis and concanavalin A staining. All proteins had high mannose and/or hybrid-type N-glycans, as indicated by the fact that they were sensitive to endoglycosidase H digestion. Three of these cytosolic glycoproteins were identified as cathepsin D, a lysosomal protease, by tryptic digestion and nano liquid chromatography electrospray ionization quadrupole time of flight mass spectrometry. The increase of cytosolic cathepsin D during aging was not due to lysosomal membrane disruption, as shown by the fact that the activities of beta-hexosaminidase and beta-glucuronidase, other lysosomal enzymes, did not increase in the cytosolic fraction. Although the total amount of cathepsin D increased during aging, the amount of cathepsin D in the microsomal fraction did not change, indicating a selective increase of cytosolic cathepsin D. This phenomenon was also observed in the hippocampus, cerebellum, kidney, liver, and spleen. Based on these results, we propose that cytosolic cathepsin D is a new biomarker of aging.


British Journal of Cancer | 2002

Inhibition of proliferation and induction of differentiation of glioma cells with Datura stramonium agglutinin

Tasuku Sasaki; K Yamazaki; Takao Yamori; Tamao Endo

We found that a lectin, Datura stramonium agglutinin, induced irreversible differentiation in C6 glioma cells. The differentiated cells had long processes, a low rate of proliferation and a high content of glial fibrillary acidic protein. When the medium was replaced with Datura stramonium agglutinin-free medium after 1 h, cell proliferation continued to be inhibited. Experiments with several other lectins indicated that both recognition of linear N-acetyllactosamine repeats and recognition of multiantennary units of cell-surface glycans were required for the inhibition of C6 proliferation. Proliferation of four human glial tumour cells was also inhibited by Datura stramonium agglutinin. Further, these differentiated human glial tumour cells had long processes and a high content of glial fibrillary acidic protein similar to differentiated C6 glioma cells. Taken together, these observations suggest that Datura stramonium agglutinin may be useful as a new therapy for treating glioma without side effects.

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Hiroshi Manya

National Institute of Genetics

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Tosifusa Toda

Yokohama City University

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