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Yoshiyuki Suzuki - One of the best experts on this subject based on the ideXlab platform.

  • Chemical Chaperone treatment for galactosialidosis effect of noev on β galactosidase activities in fibroblasts
    Brain & Development, 2016
    Co-Authors: Mohammad Arif Hossain, Katsumi Higaki, Michiko Shinpo, Eiji Nanba, Keiichi Ozono, Yoshiyuki Suzuki, Yoshiyuki Suzuki, Katsumi Higaki, Eiji Nanba, Norio Sakai
    Abstract:

    Abstract Introduction Galactosialidosis is a rare lysosomal storage disease caused by a combined deficiency of G M1 β-galactosidase (β-gal) and neuraminidase secondary to a defect of a lysosomal enzyme protective protein/cathepsin A (PPCA) and mutation in CTSA gene. Three subtypes are recognized: early infantile, late infantile, and juvenile/adult. There is no specific therapy for patients with galactosialidosis at this time. Objectives The aim of this study was to determine the Chaperone effect of N -octyl-4-epi-β-valienamine (NOEV) on β-gal proteins in skin fibroblasts of PPCA-deficit patients. Methods β-Gal and neuraminidase activities were measured for the diagnosis of the patients with galactosialidosis. Western blotting for PPCA protein and direct sequencing for CTSA gene were performed. Cultured skin fibroblast were treated with NOEV. Results We report four novel patients with galactosialidosis: one had the early infantile form and the other three had the juvenile/adult form. We found that NOEV stabilized β-gal activity in lysate from cultured skin fibroblasts from these patients. Treatment with NOEV significantly enhanced β-gal activity in cultured skin fibroblasts in the absence of PPCA. Conclusions Our results indicate the possibility that NOEV Chaperone therapy might have a beneficial effect, at least in part, for patients with galactosialidosis.

  • candidate molecules for Chemical Chaperone therapy of gm1 gangliosidosis
    Future Medicinal Chemistry, 2013
    Co-Authors: Katsumi Higaki, Yoshiyuki Suzuki, Haruaki Ninomiya, Eiji Nanba
    Abstract:

    A growing body of evidence suggests that misfolding of a mutant protein followed by its aggregation or premature degradation in the endoplasmic reticulum is one of the main mechanisms that underlie inherited neurodegenerative diseases, including lysosomal storage diseases. Chemical or pharmacological Chaperones are small molecules that bind to and stabilize mutant lysosomal enzyme proteins in the endoplasmic reticulum. A number of Chaperone compounds for lysosomal hydrolases have been identified in the last decade. They have gained attention because they can be orally administrated, and also because they can penetrate the blood–brain barrier. In this article, we describe two Chaperone candidates for the treatment of GM1-gangliosidosis. We also discuss the future direction of this strategy targeting other lysosomal storage diseases as well as protein misfolding diseases in general.

  • lysosomal accumulation of trk protein in brain of gm1 gangliosidosis mouse and its restoration by Chemical Chaperone
    Journal of Neurochemistry, 2011
    Co-Authors: Ayumi Takamura, Junichiro Matsuda, Yoshiyuki Suzuki, Katsumi Higaki, Haruaki Ninomiya, Masami Iida, Kousaku Ohno, Tomoko Takai, Eiji Nanba
    Abstract:

    J. Neurochem. (2011) 118, 399–406. Abstract GM1-gangliosidosis is a fatal neurodegenerative disorder caused by deficiency of lysosomal acid β-galactosidase (β-gal). Accumulation of its substrate ganglioside GM1 (GM1) in lysosomes and other parts of the cell leads to progressive neurodegeneration, but underlying mechanisms remain unclear. Previous studies demonstrated an essential role for interaction of GM1 with tropomyosin receptor kinase (Trk) receptors in neuronal growth, survival and differentiation. In this study we demonstrate accumulation of GM1 in the cell-surface rafts and lysosomes of the β-gal knockout (β-gal−/−) mouse brain association with accumulation of Trk receptors and enhancement of its downstream signaling. Immunofluorescence and subcellular fractionation analysis revealed accumulation of Trk receptors in the late endosomes/lysosomes of the β-gal−/− mouse brain and their association with ubiquitin and p62. Administration of a Chemical Chaperone to β-gal−/− mouse expressing human mutant R201C protein resulted in a marked reduction of intracellular storage of GM1 and phosphorylated Trk. These findings indicate that GM1 accumulation in rafts causes activation of Trk signaling, which may participate in the pathogenesis of GM1-gangliosidosis.

  • Chemical Chaperone therapy: Luciferase assay for screening of β-galactosidase mutations
    Molecular Genetics and Metabolism, 2010
    Co-Authors: Linjing Li, Yoshiyuki Suzuki, Seiichiro Ogawa, Katsumi Higaki, Haruaki Ninomiya, Zhuo Luan, Masami Iida, Kousaku Ohno, Eiji Nanba
    Abstract:

    Abstract β-Galactosidosis is a group of disorder based on heterogeneous mutations of GLB1 gene coding for the lysosomal acid β-galactosidase (β-gal). A decrease of the β-gal enzyme activity results in progressive accumulation of substrates in somatic cells, particularly in neurons, leading to severe neuronal dysfunction. We have previously reported that N -octyl-4-epi-β-valienamine (NOEV), a Chemical Chaperone compound, stabilized various mutant human β-gal proteins and increased residual enzyme activities in cultured fibroblasts from human patients. These data proved a potential therapeutic benefit of Chemical Chaperone therapy for patients with missense β-gal. This effect is mutation specific. In this study, we have established a sensitive luciferase-based assay for measuring Chaperone effect on mutant human β-gal. A dinoflagellate luciferase (Dluc) cDNA was introduced to the C-terminus of human β-gal. When COS7 cells expressing the Dluc-tagged human R201C β-gal was treated with NOEV, there happened a remarkable increase of the mutant β-gal activity. In the presence of NH 4 Cl, luciferase level in the medium increased in parallel with the enzyme activity in cell lysates. We also found that proteasome inhibitors enhance Chaperone effect of NOEV. These results demonstrate that the luciferase-based assay is a reliable and convenient method for screening and evaluation of Chaperone effects on human β-gal mutants, and that it will be a useful tool for finding novel Chaperone compounds in the future study.

  • molecular basis of Chemical Chaperone effects of n octyl β valienamine on human β glucosidase in low neutral ph conditions
    Journal of Proteomics & Bioinformatics, 2010
    Co-Authors: Katsuyuki Yugi, Yoshiyuki Suzuki, Seiichiro Ogawa, Yasubumi Sakakibara
    Abstract:

    Chemical Chaperone therapy is a strategy for restoring the activities of mutant lysosomal hydrolases. This therapy involves Chemical compounds binding to the dysfunctional enzymes. The Chemical Chaperones for lysosomal hydrolases are anticipated to stabilize folding of target enzymes by binding at neutral pH and rescuing enzyme activities by dissociation in acidic conditions after transport to lysosome. However, the molecular basis describing the mechanism of action of Chemical Chaperones has not been analysed sufficiently. Here we present results derived from molecular dynamics simulations showing that the binding free energy between human ?-glucosidase and its known Chemical Chaperone, N-octyl-?-valienamine (NOV), is lower at pH 7 than at pH 5. This observation is consistent with the hypothetical activity of Chemical Chaperones. The pH conditions were represented as differences in the protonation states of ionizable residues which were determined from predicted pKa values. The binding free energy change is negatively correlated to the number of hydrogen bonds (H-bonds) formed between GLU235, the acid/base catalyst of the enzyme, and the N atom of NOV. At pH 7, NOV is inserted further into the active site than at pH 5. Consequently, this provides an increase in the number of H-bonds formed. Thus, we conclude that the dissociation of NOV from ?-glucosidase at pH 5 occurs due to an increase in the binding free energy change caused by protonation of several residues which decreases the number of H-bonds formed between NOV and the enzyme.

Masayuki Itoh - One of the best experts on this subject based on the ideXlab platform.

  • Chemical Chaperone therapy clinical effect in murine gm1 gangliosidosis
    Annals of Neurology, 2007
    Co-Authors: Yoshiyuki Suzuki, Kazuhiro Takimoto, Junichiro Matsuda, Satoshi Ichinomiya, Mieko Kurosawa, Masato Ohkubo, Hiroshi Watanabe, Hiroyuki Iwasaki, Yoko Noguchi, Masayuki Itoh
    Abstract:

    : Certain low-molecular-weight substrate analogs act both as in vitro competitive inhibitors of lysosomal hydrolases and as intracellular enhancers (Chemical Chaperones) by stabilization of mutant proteins. In this study, we performed oral administration of a Chaperone compound N-octyl-4-epi-beta-valienamine to G(M1)-gangliosidosis model mice expressing R201C mutant human beta-galactosidase. A newly developed neurological scoring system was used for clinical assessment. N-Octyl-4-epi-beta-valienamine was delivered rapidly to the brain, increased beta-galactosidase activity, decreased ganglioside G(M1), and prevented neurological deterioration within a few months. No adverse effect was observed during this experiment. N-Octyl-4-epi-beta-valienamine will be useful for Chemical Chaperone therapy of human G(M1)-gangliosidosis.

  • Chemical Chaperone therapy clinical effect in murine gm1 gangliosidosis
    Annals of Neurology, 2007
    Co-Authors: Yoshiyuki Suzuki, Kazuhiro Takimoto, Junichiro Matsuda, Satoshi Ichinomiya, Mieko Kurosawa, Masato Ohkubo, Hiroshi Watanabe, Hiroyuki Iwasaki, Yoko Noguchi, Masayuki Itoh
    Abstract:

    Certain low-molecular-weight substrate analogs act both as in vitro competitive inhibitors of lysosomal hydrolases and as intracellular enhancers (Chemical Chaperones) by stabilization of mutant proteins. In this study, we performed oral administration of a Chaperone compound N-octyl-4-epi-β-valienamine to GM1-gangliosidosis model mice expressing R201C mutant human β-galactosidase. A newly developed neurological scoring system was used for clinical assessment. N-Octyl-4-epi-β-valienamine was delivered rapidly to the brain, increased β-galactosidase activity, decreased ganglioside GM1, and prevented neurological deterioration within a few months. No adverse effect was observed during this experiment. N-Octyl-4-epi-β-valienamine will be useful for Chemical Chaperone therapy of human GM1-gangliosidosis. Ann Neurol 2007

  • Chemical Chaperone therapy for brain pathology in gm1 gangliosidosis
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Junichiro Matsuda, Yoshie Yamamoto, Kazuhiro Takimoto, Seiichiro Ogawa, Akira Noguchi, Akihiro Oshima, Yosuke Yasuda, Yuji Matsuzaki, Masayuki Itoh, Osamu Suzuki, Seiichiro Ogawa
    Abstract:

    We synthesized a galactose derivative, N-octyl-4-epi-β-valienamine (NOEV), for a molecular therapy (Chemical Chaperone therapy) of a human neurogenetic disease, β-galactosidosis (GM1-gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal β-galactosidase in vitro. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile GM1-gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. ImmunohistoChemical stain revealed a decrease in the amount of GM1 and GA1 in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass bioChemical analysis did not show the substrate reduction observed histoChemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical Chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.

  • Chemical Chaperone therapy for brain pathology in gm1 gangliosidosis
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Junichiro Matsuda, Yoshie Yamamoto, Kazuhiro Takimoto, Akira Noguchi, Akihiro Oshima, Yosuke Yasuda, Yuji Matsuzaki, Masayuki Itoh, Osamu Suzuki, Seiichiro Ogawa
    Abstract:

    We synthesized a galactose derivative, N-octyl-4-epi-β-valienamine (NOEV), for a molecular therapy (Chemical Chaperone therapy) of a human neurogenetic disease, β-galactosidosis (GM1-gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal β-galactosidase in vitro. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile GM1-gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. ImmunohistoChemical stain revealed a decrease in the amount of GM1 and GA1 in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass bioChemical analysis did not show the substrate reduction observed histoChemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical Chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.

Timothy E. Weaver - One of the best experts on this subject based on the ideXlab platform.

  • 4 phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein c
    American Journal of Respiratory Cell and Molecular Biology, 2012
    Co-Authors: Gareth Stewart, Ross Ridsdale, Emily P. Martin, Karunyakanth Mandapaka, Timothy E. Weaver
    Abstract:

    Mutations in the SFTPC gene, encoding surfactant protein-C (SP-C), are associated with interstitial lung disease (ILD). Knowledge of the intracellular fate of mutant SP-C is essential in the design of therapies to correct trafficking/processing of the proprotein, and to prevent the formation of cytotoxic aggregates. We assessed the potential of a Chemical Chaperone to correct the trafficking and processing of three disease-associated mutant SP-C proteins. HEK293 cells were stably transfected with wild-type (SP-C(WT)) or mutant (SP-C(L188Q), SP-C(Δexon4), or SP-C(I73T)) SP-C, and cell lines with a similar expression of SP-C mRNA were identified. The effects of the Chemical Chaperone 4-phenylbutyric acid (PBA) and lysosomotropic drugs on intracellular trafficking to the endolysosomal pathway and the subsequent conversion of SP-C proprotein to mature peptide were assessed. Despite comparable SP-C mRNA expression, proprotein concentrations varied greatly: SP-C(I73T) was more abundant than SP-C(WT) and was localized to the cell surface, whereas SP-C(Δexon4) was barely detectable. In contrast, SP-C(L188Q) and SP-C(WT) proprotein concentrations were comparable, and a small amount of SP-C(L188Q) was localized to the endolysosomal pathway. PBA treatment restored the trafficking and processing of SP-C(L188Q) to SP-C(WT) concentrations, but did not correct the mistrafficking of SP-C(I73T) or rescue SP-C(Δexon4). PBA treatment also promoted the aggregation of SP-C proproteins, including SP-C(L188Q). This study provides proof of the principle that a Chemical Chaperone can correct the mistrafficking and processing of a disease-associated mutant SP-C proprotein.

  • 4-Phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein-C.
    American journal of respiratory cell and molecular biology, 2012
    Co-Authors: Gareth A. Stewart, Ross Ridsdale, Emily P. Martin, Karunyakanth Mandapaka, Timothy E. Weaver
    Abstract:

    Mutations in the SFTPC gene, encoding surfactant protein–C (SP-C), are associated with interstitial lung disease (ILD). Knowledge of the intracellular fate of mutant SP-C is essential in the design of therapies to correct trafficking/processing of the proprotein, and to prevent the formation of cytotoxic aggregates. We assessed the potential of a Chemical Chaperone to correct the trafficking and processing of three disease-associated mutant SP-C proteins. HEK293 cells were stably transfected with wild-type (SP-CWT) or mutant (SP-CL188Q, SP-CΔexon4, or SP-CI73T) SP-C, and cell lines with a similar expression of SP-C mRNA were identified. The effects of the Chemical Chaperone 4-phenylbutyric acid (PBA) and lysosomotropic drugs on intracellular trafficking to the endolysosomal pathway and the subsequent conversion of SP-C proprotein to mature peptide were assessed. Despite comparable SP-C mRNA expression, proprotein concentrations varied greatly: SP-CI73T was more abundant than SP-CWT and was localized to th...

Stangl Herbert - One of the best experts on this subject based on the ideXlab platform.

  • Scientific Reports / The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a Chemical Chaperone
    Nature, 2017
    Co-Authors: Röhrl Clemens, Mikula Mario, Eigner Karin, Filik Yüksel, Mark Florian, Schütz Birgit, Klambauer Günter, Moriggl Richard, Hengstschläger Markus, Stangl Herbert
    Abstract:

    The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAFV600E-mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells. Increased UPR-activity was associated with increased flexibility to cope with ER stress. The activity of the ATF6- and the PERK-, but not the IRE-pathway, correlated with poor survival in melanoma patients. Using whole-genome expression analysis, we show that the UPR is an inducer of FGF1 and FGF2 expression and cell migration. Antagonization of the UPR using the Chemical Chaperone 4-phenylbutyric acid (4-PBA) reduced FGF expression and inhibited cell migration and viability. Consistently, FGF expression positively correlated with the activity of ATF6 and PERK in human melanomas. We conclude that chronic UPR stimulates the FGF/FGF-receptor signalling axis and promotes melanoma progression. Hence, the development of potent Chemical Chaperones to antagonize the UPR might be a therapeutic approach to target melanoma.(VLID)463730

Yasuyuki Nomura - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of synthetic naphthalene derivatives as novel Chemical Chaperones that mimic 4-phenylbutyric acid.
    Bioorganic & medicinal chemistry letters, 2015
    Co-Authors: Seisuke Mimori, Yasunobu Okuma, Masayuki Kaneko, Koichi Kawada, Yasuyuki Nomura, Yasuoki Murakami, Yukari Koshikawa, Yu Mashima, Katsuyoshi Mitsunaga, Tetsuto Kanzaki
    Abstract:

    The Chemical Chaperone 4-phenylbutyric acid (4-PBA) has potential as an agent for the treatment of neurodegenerative diseases. However, the requirement of high concentrations warrants Chemical optimization for clinical use. In this study, novel naphthalene derivatives with a greater Chemical Chaperone activity than 4-PBA were synthesized with analogy to the benzene ring. All novel compounds showed Chemical Chaperone activity, and 2 and 5 possessed high activity. In subsequent experiments, the protective effects of the compounds were examined in Parkinson’s disease model cells, and low toxicity of 9 and 11 was related to amphiphilic substitution with naphthalene.

  • 4 phenylbutyric acid protects against neuronal cell death by primarily acting as a Chemical Chaperone rather than histone deacetylase inhibitor
    Bioorganic & Medicinal Chemistry Letters, 2013
    Co-Authors: Seisuke Mimori, Yasunobu Okuma, Masayuki Kaneko, Koichi Kawada, Yasuyuki Nomura, Yasuoki Murakami, Yukari Koshikawa, Hiroyasu Ohtaka, Hiroshi Hamana
    Abstract:

    Abstract This letter describes the mechanism behind the protective effect of 4-phenylbutyric acid (4-PBA) against endoplasmic reticulum (ER) stress-induced neuronal cell death using three simple 4-(p-substituted phenyl) butyric acids (4-PBA derivatives). Their relative human histone deacetylase (HDAC) inhibitory activities were consistent with a structural model of their binding to HDAC7, and their ability to suppress neuronal cell death and activity of Chemical Chaperone in vitro. These data suggest that 4-PBA protects against neuronal cell death mediated by the Chemical Chaperone activity rather than by inhibition of histone deacetylase.

  • Discovery of Synthetic Methoxy-substituted 4-Phenylbutyric Acid Derivatives as Chemical Chaperones
    Chemistry Letters, 2013
    Co-Authors: Seisuke Mimori, Yasunobu Okuma, Masayuki Kaneko, Koichi Kawada, Yasuyuki Nomura, Yasuoki Murakami, Hiroshi Hamana
    Abstract:

    In this study, we evaluated the Chemical Chaperone activity of synthetic 4-phenylbutyric acid (4-PBA) derivatives. These derivatives have a methoxy group at the benzene ring and/or longer or shorte...

  • sodium 4 phenylbutyrate protects against cerebral ischemic injury
    Molecular Pharmacology, 2004
    Co-Authors: Xin Qi, Yasunobu Okuma, Masayuki Kaneko, Toru Hosoi, Yasuyuki Nomura
    Abstract:

    Sodium 4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid that has been used for treatment of urea cycle disorders in children, sickle cell disease, and thalassemia. It has been demonstrated recently that 4-PBA can act as a Chemical Chaperone by reducing the load of mutant or mislocated proteins retained in the endoplasmic reticulum (ER) under conditions associated with cystic fibrosis and liver injury. In the present study, we evaluated the neuroprotective effect of 4-PBA on cerebral ischemic injury. Pre- or post-treatment with 4-PBA at therapeutic doses attenuated infarction volume, hemispheric swelling, and apoptosis and improved neurological status in a mouse model of hypoxia-ischemia. Moreover, 4-PBA suppressed ER-mediated apoptosis by inhibiting eukaryotic initiation factor 2alpha phosphorylation, CCAAT/enhancer-binding protein homologous protein induction, and caspase-12 activation. In neuroblastoma neuro2a cells, 4-PBA reduced caspase-12 activation, DNA fragmentation, and cell death induced by hypoxia/reoxygenation. It protected against ER stress-induced but not mitochondria-mediated cell death. Additionally, 4-PBA inhibited the expression of inducible nitric-oxide synthase and tumor necrosis factor-alpha in primary cultured glial cells under hypoxia/reoxygenation. These results indicate that 4-PBA could protect against cerebral ischemia through inhibition of ER stress-mediated apoptosis and inflammation. Therefore, the multiple actions of 4-PBA may provide a strong effect in treatment of cerebral ischemia, and its use as a Chemical Chaperone would provide a novel approach for the treatment of stroke.