Misc - HISAHARA Shin

Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination

S Hisahara, H Okano, M Miura

NEUROSCIENCE RESEARCH ( ELSEVIER SCI IRELAND LTD )  46 ( 4 ) 387 - 397  2003.08

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Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. NIS is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory and cytokines that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, nitric oxide, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. Transgenic mice that express the anti-apoptotic protein specifically in OLGs and caspase-11-deficient mice are significantly resistant to EAE induction. Histopathological analyses show that the number of caspase-activated OLGs and dead OLGs are reduced in the CNS of these mice. The numbers of infiltrating immune cells and the amounts of cytokines are also markedly reduced in EAE lesions. Therefore, caspase-mediated OLG death leads to the exacerbation of demyelination and the deterioration of neurological manifestations by inducing local inflammatory events. (C) 2003 Elsevier Science Ireland Ltd and Japan Neuroscience Society. All rights reserved.

DOI PubMed CiNii

Functional analysis of SIR2

Yoshiyuki Horio, Shin Hisahara, Jun Sakamoto

Folia Pharmacologica Japonica   122 ( 1 ) 30 - 32  2003

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The yeast silent information regulator 2 (Sir2) is an NAD-dependent histone deacetylase and silences transcription at the mating type loci, telomeres and the ribosomal DNA. Over-expression of Sir2 extends the life span of yeast and C. elegans, while Sir2 knockout shortened yeast life span to about 50%. Mammalian cells also express several Sir2 homologues. However, most of physiological functions of Sir2 homologues seem to be unknown. We found that Sir2α(SIRT1) was highly expressed during embryogenesis. In the adult mouse brain, ependymal cells and some cells of subventricular zone expressed Sir2α. To identify proliferating neural cells in the adult brain, BrdU was administered in the drinking water for 2 weeks. BrdU-positive and nestin-positive cells expressed Sir2α. Furthermore, neurosphere cultured from E14 mouse striatum expressed Sir2α. The expression of Sir2α in neurosphere disappeared after differentiation. Nicotinamide, splitomicin and sirtinol, potent inhibitors of Sir2α, inhibited the growth of neurosphere. FACS analysis showed that sirtinol did not increase sub-G1 population of cells. Differentiation of neuroshere into neuron and oligodendrocyte was inhibited by the addition of nicotinamide, splitomicin or sirtinol in the differentiation medium. These results suggest that Sir2α has a pivotal role in the proliferation and differentiation of neural stem cells.

PubMed

Molecular analysis of aging; NAD dependent histone deacetylase, SIR2

Yoshiyuki Horio, Jun Sakamoto, Shin Hisahara

Sapporo Medical Journal   71 ( 3-4 ) 13 - 18  2002.08

Book review, literature introduction, etc.  

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SIR2 and its homologues are newly identified nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases. Yeast (Saccharomyces cerevisiae) SIR2 silences transcription at silent mating loci, teromeres and ribosomal DNA (rDNA), and that also suppresses recombination in rDNA. Yeast and mammalian SIR2 homologue (SIR2α) was found to specifically deacetylate acetylated lysine residues of histone H3 and H4 in a NAD-dependent manner. The deacetylation of histones has been identified as important for silencing. Interestingly, increase in dosages of SIR2 gene extended the life span in yeast and Caenorhabditis elegans. Although recent studies showed that Sir2α directly binds and deacetylates p53 to repress p53-dependent apoptosis, the distribution and physiological functions of SIR2 family in mammals still remain to be elucidated. We found that SIR2α and SIR3, both of which are mammalian SIR2 homologues, are expressed in neural stem cells. The expression of these SIRs promptly disappeared after differentiation. We assume that these SIRs may play a significant role in the proliferation and/or differentiation of neural stem cells.

Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination

S Hisahara, JY Yuan, T Momoi, H Okano, M Miura

JOURNAL OF EXPERIMENTAL MEDICINE ( ROCKEFELLER UNIV PRESS )  193 ( 1 ) 111 - 122  2001.01

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Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11-deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11-deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspase-11 and -3 and leads to the demyelination observed in EAE.

DOI

Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune-mediated demyelination

S Hisahara, T Araki, F Sugiyama, K Yagami, M Suzuki, K Abe, K Yamamura, J Miyazaki, T Momoi, T Saruta, CCA Bernard, H Okano, M Miura

EMBO JOURNAL ( OXFORD UNIV PRESS )  19 ( 3 ) 341 - 348  2000.02

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The mechanisms underlying oligodendrocyte (OLG) loss and the precise roles played by OLG death in human demyelinating diseases such as multiple sclerosis (MS), and in the rodent model of MS, experimental autoimmune encephalomyelitis (EAE), remain to be elucidated. To clarify the involvement of OLG death in EAE, we have generated transgenic mice that express the baculovirus anti-apoptotic protein p35 in OLGs through the Cre-loxP system. OLGs from cre/p35 transgenic mice mere resistant to tumor necrosis factor-alpha-, anti-Fas antibody- and interferon-gamma-induced cell death. cre/p35 transgenic mice mere resistant to EAE induction by immunization with the myelin oligodendrocyte glycoprotein, The numbers of infiltrating T cells and macrophages/microglia in the EAE lesions were significantly reduced, as were the numbers of apoptotic OLGs expressing the activated form of caspase-3. Thus, inhibition of apoptosis in OLGs by p35 expression alleviated the severity of the neurological manifestations observed in autoimmune demyelinating diseases.

DOI

Effects of neurotrophins in TNF induced oligodendrocyte cell death

TAKANO R., HISAHARA S., OKANO H., MIURA M.

日本分子生物学会年会プログラム・講演要旨集   21   568 - 568  1998.12

CiNii

Caenorhabditis elegans anti-apoptotic gene ced-9 prevents ced-3-induced cell death in Drosophila cells

S Hisahara, H Kanuka, S Shoji, S Yoshikawa, H Okano, M Miura

JOURNAL OF CELL SCIENCE ( COMPANY OF BIOLOGISTS LTD )  111   667 - 673  1998.03

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ced-9, a member of the bcl-2 gene family in Caenorhabditis elegans plays a central roles in preventing cell death in norms. Overexpression of human bcl-2 can partially prevent cell death in C. elegans. However, it remains to be elucidated whether ced-9 can regulate cell death when expressed in other organisms. We demonstrated that the CED-9 protein is co-localized with BCL-2 in COS cells and Drosophila Schneider's L2 (SL2) cells, suggesting that the site of CED-9 action is located to specific cytoplasmic compartments. Overexpression of ced-9 only poorly protected cells from the death induced by ced-3 in HeLa cells, but ced-9 significantly reduced the cell death induced by ced-3 in Drosophila SL2 cells. Furthermore, apoptosis of SL2 cells that was induced by a Drosophila cell-death gene, reaper, was shown to be partially prevented by ced-9, bcl-2 and bcl-xL. These results suggest that the signaling pathway that is required for the anti-apoptotic function of bcl-2 family members, including ced-9, is conserved in Drosophila cells. In addition, SL2 cells provide a unique systems for dissecting the main machinery of cell death.

ICE/CED-3 family executes oligodendrocyte apoptosis by tumor necrosis factor

S Hisahara, S Shoji, H Okano, M Miura

JOURNAL OF NEUROCHEMISTRY ( LIPPINCOTT-RAVEN PUBL )  69 ( 1 ) 10 - 20  1997.07

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Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes (OLGs) in multiple sclerosis (MS), We report here the involvement of the interleukin 1 beta-converting enzyme (ICE)/Caenorhabditis elegans gene ced-3 (CED-3) family in TNF-mediated cell death of OLGs. The addition of TNF-alpha to primary cultures of OLGs that express ice and cpp32 significantly decreased the number of live OLGs in 72 h. DNA fragmentation was detected in TNF-treated OLGs at 36 h with the terminal deoxynucleotidyl transferase dUTP nick end-labeling assay. Benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene, an inhibitor of the ICE/CED-3 family that shows p35-like inhibitory specificity, protected against the TNF-induced cell death of OLGs. Furthermore, acetyl-YVAD-CHO (a specific inhibitor of ICE-like proteases) as well as acetyl-DEVD-CHO (a specific inhibitor of CPP32-like proteases) enhanced the survival of OLGs treated with TNF-alpha, indicating that ICE- and the CPP32-medialed cell death pathways are activated in TNF-induced OLG cell death. Our results suggest that the inhibition of ICE/CED-3 proteases may be a novel approach to treat neurodegenerative diseases such as MS.

DOI