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G protein-coupled receptor 30 contribute to improve remyelination after cuprizone-induced demyelination
e198
Abstracts / Neuroscience Research 68S (2010) e109–e222
VEGF-dependent neuroprotection leads to the select degeneration of motor neurons. In addition, apelin highly expresses in spinal cord of human and rat. In this study, we examined whether apelin is an endogenous neuroprotective factor in spinal cord by using G93A-SOD1 mouse model of amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disorder in which selective loss of motoneurons in spinal cord leads to progressive paralysis. In CNS tissues of wild-type mice, the highest expressions of either apelin or APJ mRNAs were detected in spinal cord. The APJ immunoreactive cells were found in neuronal cell bodies located in gray matter in spinal cord. G93A-SOD1 mice began to show signs of hind limb weakness at 9 weeks age and paralysis at 18 weeks age. Although apelin mRNA expression in spinal cord of wild-type mice was not changed from 4–18 weeks age, that of G93ASOD1 mice was reduced along with the paralytic phenotype. Furthermore, we examined whether apelin protects against neuronal death by using rat primary neurons. Apelin alone hardly protected hydrogen peroxide-induced neuronal death on primary neurons. However, apelin enhanced the protective effect of VEGF for the neuronal death. These results suggest that apelin may delay the progression of ALS by enhancing the neuronal protective effect of VEGF.
cyte. In this study, we found that the putative membrane estrogen receptor, G protein-coupled receptor 30 (GPR 30) was expressed in perikaryon of oligodendrocyte in rat spinal cord and corpus callosum. Moreover, GPR 30 was expressed through OL differentiation and promyelinating stage in primary oligodendrocyte culture derived from rat spinal cord and brain. The expression of GPR 30 in oligodendrocyte was confirmed by Western blot analysis, and shown in a 38 kDa form. We evaluated the role of the signaling via GPR 30 in promyelination in the cuprizone-provoked demyelination rat model, which induces oligodendroglial cell death and downregulation of myelin genes. After cuprizone diet, the model rat was treated with G1, a specific agonist for GPR 30, by repeated subcutaneous injection. Histological examination of corpus callosum with makers of mature oligodendrocyte (O4, RIP and GSTpai) displayed enhancement oligodendrocyte maturation in cuprizone- rat corpus callosum treated with G1. This study is the first evaluation that G1 is efficient in mediating the improvement of remyelination in oligodendrocyte, and may provide a novel therapeutical strategy for the treatment of multiple sclerosis.
doi:10.1016/j.neures.2010.07.2446
P1-o24 Exploring the role of Cystatin F in murine demyelinating models
P1-o21 Gp78 promotes sod1 degradation Guanghui Wang , Zheng Ying, Hongfeng Wang, Huadong Fan School of Life Sciences, University of Science & Technology of China SOD1 is a proteins in association with amyotrophic lateral sclerosis (ALS). Both normal and mutant types of SOD1 are degraded by the proteasome. It was recently reported that it is associated with the ER (endoplasmic reticulum). Mammalian gp78 is an E3 ubiquitin ligase involved in ERAD (ERassociated degradation). Here, we show that gp78 interacts with both wild type and mutant SOD1. Overexpression of gp78 promotes the ubiquitination and degradation of them, whereas knockdown of gp78 stabilizes them. Moreover, gp78 represses aggregate formation of mutant SOD1 and protect cells against mutant SOD1-induced cell death. Furthermore, gp78 is increased in cells transfected with these two mutant proteins as well as in ALS mice. Thus, our results suggest that gp78 functions in the regulation of SOD1 to target them for ERAD. doi:10.1016/j.neures.2010.07.2447
P1-o22 Cytochrome Oxidase distribution in monkey brain agreed with mitochondrial diseases Hiroko Kosaki 1 , Mortimer Mishkin 2 1
Tokyo Hospital, National Printing Bureau, Tokyo, Japan 2 NIMH,Bethesda, USA Cytochrome Oxidase is a metabolic enzyme and is distributed mainly on mitochondria, To investigate the pathology of mitochondrial disease, we examined the distribution of Cytochrome Oxidase (CO) on macaque brain by Wong-Riley method. The results were, in the central nervous system, CO were distributed in large amount in motor cortex, cingulate cortex, primary visual cortex, primary auditory cortex, primary somatosenstory cortex, primary gustatory cortex, LGB, MGB, ventral thalamus, pulvinar, anterior thalamus, central thalamus, mammalian body, hippocampus, amygdara, putamen, caudate nucleus, brain stem, and cerebellum. These distribution of CO may explain various fragile portion in ventral nervous system for mitochondrial diseases.
doi:10.1016/j.neures.2010.07.2449
Takahiro Shimizu 1,2 , Kenji F. Tanaka 1,2 , Jianmei Ma 3 , Kazuhiro Ikenaka 1,2 1
The Graduate University for Advanced Studies, Hayama, Japan 2 National Institute for Physiological Sciences/Division of Neurobiology and Bioinformatics, Okazaki, Japan 3 Department of Anatomy, Dalian Medical University, Dalian, China Myelin is a membrane structure enabling saltatory conduction of action potential and is formed by oligodendrocytes in the CNS. Multiple sclerosis (MS) is one of demyelinating diseases. In chronic demyelinating lesions in the MS patient brain, oligodendrocyte precursor cells (OPCs) are found abundantly, and moreover pre-myelinating oligodendrocytes are also found, but they somehow fail to achieve terminal differentiation into myelin-forming oligodendrocytes. In our previous study on the lineage tracing of Olig2+ cells in a murine demyelinating disease model, we found that OPCs did differentiate into oligodendrocytes, but that oligodendrocytes degenerated during maturation. Therefore, it was suggested that the environment around OPCs and oligodendrocytes were poor to support the terminal differentiation. It has been reported that the TNF-alpha pathway is implicated in MS susceptibility through the observations in human clinical studies: treatment with monoclonal antibodies to TNF-alpha may trigger acute episodes of CNS inflammation in subjects with MS. Thus, we focused on the behavior of microglia, the major TNF-alpha producing cells in the CNS, in the demyelinating brain. We have previously found that Cystatin F, which is a cysteine protease inhibitor, is expressed in microglia when remyelination is occurring and the expression decreased when chronic demyelinated lesions appeared. It is reported that Cystatin F binds and inhibit the function of Cathepsin C, a cysteine protease. Furthermore, Cathepsin C is involved in the alternative pathway for the activation of TNF-alpha and IL-1 beta. In this study, we focused on Cathepsin C. The expression pattern of Cathepsin C was similar to that of Cystatin F. We found that Cathepsin C is expressed in microglia and the location of cathepsin C overlapped with that of cystatin F. Thus Cystatin F is suggested to decrease the activation of pro-inflammatory cytokines by inhibiting Cathepsin C. doi:10.1016/j.neures.2010.07.2450
doi:10.1016/j.neures.2010.07.2448
P1-o25 Moduratory effect of Microsomal prostaglandin E synthase-1 on multiple sclerosis
P1-o23 G protein-coupled receptor 30 contribute to improve remyelination after cuprizone-induced demyelination
Takako Takemiya 1 , Chisen Takeuchi 1,2 , Yoh Matsumoto 3 , Kuniko Kohyama 3 , Satoshi Uematsu 4 , Shizuo Akira 4 , Kanato Yamagata 5 , Kumiko Fumisawa 1
Dept Anatomy and Cell Science, Kansai Medical University, Osaka 2 Dept Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kyoto
Medical Research Inst., Tokyo Women’s Med. Univ 2 Dept. Neurol., Tokyo Women’s Med. Univ 3 Dept. Mol. Neuropatho., Tokyo Metropo. Inst. Neurosci 4 Dept. Host Defence, Research Inst., Microbial Dis., Osaka Univ 5 Dept. Pharmacol., Tokyo Metropo. Inst. Neurosci
Estradiol is thought to exert neuroprotective and promyelinating actions. The therapeutic effect has been especially shown in animal models of multiple sclerosis, in which the myelin sheath is specifically destroyed in the central nervous system. However, it remains unproven whether estradiol is directly affected in remyelination via the myelin producing cell, oligodendro-
Prostaglandin E2 (PGE2 ) is an influential modulator. In the brain, PGE2 is involved in numerous pathological processes such as fever, seizure, and cerebral infarction. Inducible PGE2 is synthesized from arachidonic acid by cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) in various cells and tissues. Multiple sclerosis (MS) is the most common central
Yukie Hirahara 1 , Ken-ichi Matsuda 2 , Keiko Takanami 2 , Mitsuhiro Kawata 2 , Hisao Yamada 1 1
1
Abstracts / Neuroscience Research 68S (2010) e109–e222
VEGF-dependent neuroprotection leads to the select degeneration of motor neurons. In addition, apelin highly expresses in spinal cord of human and rat. In this study, we examined whether apelin is an endogenous neuroprotective factor in spinal cord by using G93A-SOD1 mouse model of amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disorder in which selective loss of motoneurons in spinal cord leads to progressive paralysis. In CNS tissues of wild-type mice, the highest expressions of either apelin or APJ mRNAs were detected in spinal cord. The APJ immunoreactive cells were found in neuronal cell bodies located in gray matter in spinal cord. G93A-SOD1 mice began to show signs of hind limb weakness at 9 weeks age and paralysis at 18 weeks age. Although apelin mRNA expression in spinal cord of wild-type mice was not changed from 4–18 weeks age, that of G93ASOD1 mice was reduced along with the paralytic phenotype. Furthermore, we examined whether apelin protects against neuronal death by using rat primary neurons. Apelin alone hardly protected hydrogen peroxide-induced neuronal death on primary neurons. However, apelin enhanced the protective effect of VEGF for the neuronal death. These results suggest that apelin may delay the progression of ALS by enhancing the neuronal protective effect of VEGF.
cyte. In this study, we found that the putative membrane estrogen receptor, G protein-coupled receptor 30 (GPR 30) was expressed in perikaryon of oligodendrocyte in rat spinal cord and corpus callosum. Moreover, GPR 30 was expressed through OL differentiation and promyelinating stage in primary oligodendrocyte culture derived from rat spinal cord and brain. The expression of GPR 30 in oligodendrocyte was confirmed by Western blot analysis, and shown in a 38 kDa form. We evaluated the role of the signaling via GPR 30 in promyelination in the cuprizone-provoked demyelination rat model, which induces oligodendroglial cell death and downregulation of myelin genes. After cuprizone diet, the model rat was treated with G1, a specific agonist for GPR 30, by repeated subcutaneous injection. Histological examination of corpus callosum with makers of mature oligodendrocyte (O4, RIP and GSTpai) displayed enhancement oligodendrocyte maturation in cuprizone- rat corpus callosum treated with G1. This study is the first evaluation that G1 is efficient in mediating the improvement of remyelination in oligodendrocyte, and may provide a novel therapeutical strategy for the treatment of multiple sclerosis.
doi:10.1016/j.neures.2010.07.2446
P1-o24 Exploring the role of Cystatin F in murine demyelinating models
P1-o21 Gp78 promotes sod1 degradation Guanghui Wang , Zheng Ying, Hongfeng Wang, Huadong Fan School of Life Sciences, University of Science & Technology of China SOD1 is a proteins in association with amyotrophic lateral sclerosis (ALS). Both normal and mutant types of SOD1 are degraded by the proteasome. It was recently reported that it is associated with the ER (endoplasmic reticulum). Mammalian gp78 is an E3 ubiquitin ligase involved in ERAD (ERassociated degradation). Here, we show that gp78 interacts with both wild type and mutant SOD1. Overexpression of gp78 promotes the ubiquitination and degradation of them, whereas knockdown of gp78 stabilizes them. Moreover, gp78 represses aggregate formation of mutant SOD1 and protect cells against mutant SOD1-induced cell death. Furthermore, gp78 is increased in cells transfected with these two mutant proteins as well as in ALS mice. Thus, our results suggest that gp78 functions in the regulation of SOD1 to target them for ERAD. doi:10.1016/j.neures.2010.07.2447
P1-o22 Cytochrome Oxidase distribution in monkey brain agreed with mitochondrial diseases Hiroko Kosaki 1 , Mortimer Mishkin 2 1
Tokyo Hospital, National Printing Bureau, Tokyo, Japan 2 NIMH,Bethesda, USA Cytochrome Oxidase is a metabolic enzyme and is distributed mainly on mitochondria, To investigate the pathology of mitochondrial disease, we examined the distribution of Cytochrome Oxidase (CO) on macaque brain by Wong-Riley method. The results were, in the central nervous system, CO were distributed in large amount in motor cortex, cingulate cortex, primary visual cortex, primary auditory cortex, primary somatosenstory cortex, primary gustatory cortex, LGB, MGB, ventral thalamus, pulvinar, anterior thalamus, central thalamus, mammalian body, hippocampus, amygdara, putamen, caudate nucleus, brain stem, and cerebellum. These distribution of CO may explain various fragile portion in ventral nervous system for mitochondrial diseases.
doi:10.1016/j.neures.2010.07.2449
Takahiro Shimizu 1,2 , Kenji F. Tanaka 1,2 , Jianmei Ma 3 , Kazuhiro Ikenaka 1,2 1
The Graduate University for Advanced Studies, Hayama, Japan 2 National Institute for Physiological Sciences/Division of Neurobiology and Bioinformatics, Okazaki, Japan 3 Department of Anatomy, Dalian Medical University, Dalian, China Myelin is a membrane structure enabling saltatory conduction of action potential and is formed by oligodendrocytes in the CNS. Multiple sclerosis (MS) is one of demyelinating diseases. In chronic demyelinating lesions in the MS patient brain, oligodendrocyte precursor cells (OPCs) are found abundantly, and moreover pre-myelinating oligodendrocytes are also found, but they somehow fail to achieve terminal differentiation into myelin-forming oligodendrocytes. In our previous study on the lineage tracing of Olig2+ cells in a murine demyelinating disease model, we found that OPCs did differentiate into oligodendrocytes, but that oligodendrocytes degenerated during maturation. Therefore, it was suggested that the environment around OPCs and oligodendrocytes were poor to support the terminal differentiation. It has been reported that the TNF-alpha pathway is implicated in MS susceptibility through the observations in human clinical studies: treatment with monoclonal antibodies to TNF-alpha may trigger acute episodes of CNS inflammation in subjects with MS. Thus, we focused on the behavior of microglia, the major TNF-alpha producing cells in the CNS, in the demyelinating brain. We have previously found that Cystatin F, which is a cysteine protease inhibitor, is expressed in microglia when remyelination is occurring and the expression decreased when chronic demyelinated lesions appeared. It is reported that Cystatin F binds and inhibit the function of Cathepsin C, a cysteine protease. Furthermore, Cathepsin C is involved in the alternative pathway for the activation of TNF-alpha and IL-1 beta. In this study, we focused on Cathepsin C. The expression pattern of Cathepsin C was similar to that of Cystatin F. We found that Cathepsin C is expressed in microglia and the location of cathepsin C overlapped with that of cystatin F. Thus Cystatin F is suggested to decrease the activation of pro-inflammatory cytokines by inhibiting Cathepsin C. doi:10.1016/j.neures.2010.07.2450
doi:10.1016/j.neures.2010.07.2448
P1-o25 Moduratory effect of Microsomal prostaglandin E synthase-1 on multiple sclerosis
P1-o23 G protein-coupled receptor 30 contribute to improve remyelination after cuprizone-induced demyelination
Takako Takemiya 1 , Chisen Takeuchi 1,2 , Yoh Matsumoto 3 , Kuniko Kohyama 3 , Satoshi Uematsu 4 , Shizuo Akira 4 , Kanato Yamagata 5 , Kumiko Fumisawa 1
Dept Anatomy and Cell Science, Kansai Medical University, Osaka 2 Dept Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kyoto
Medical Research Inst., Tokyo Women’s Med. Univ 2 Dept. Neurol., Tokyo Women’s Med. Univ 3 Dept. Mol. Neuropatho., Tokyo Metropo. Inst. Neurosci 4 Dept. Host Defence, Research Inst., Microbial Dis., Osaka Univ 5 Dept. Pharmacol., Tokyo Metropo. Inst. Neurosci
Estradiol is thought to exert neuroprotective and promyelinating actions. The therapeutic effect has been especially shown in animal models of multiple sclerosis, in which the myelin sheath is specifically destroyed in the central nervous system. However, it remains unproven whether estradiol is directly affected in remyelination via the myelin producing cell, oligodendro-
Prostaglandin E2 (PGE2 ) is an influential modulator. In the brain, PGE2 is involved in numerous pathological processes such as fever, seizure, and cerebral infarction. Inducible PGE2 is synthesized from arachidonic acid by cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) in various cells and tissues. Multiple sclerosis (MS) is the most common central
Yukie Hirahara 1 , Ken-ichi Matsuda 2 , Keiko Takanami 2 , Mitsuhiro Kawata 2 , Hisao Yamada 1 1
1