Details of a Researcher - Furukawa, Yoshiaki

Papers - Furukawa, Yoshiaki

Division display >> ／ All the affair displays 1 - 23 of about 23

Cysteine residues in Cu,Zn-superoxide dismutase are essential to toxicity in Caenorhabditis elegans model of amyotrophic lateral sclerosis

Ogawa, Mariko, Shidara, Hisashi, Oka, Kotaro, Kurosawa, Masaru, Nukina, Nobuyuki, Furukawa, Yoshiaki

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 463 ( 4 ) 1196 - 1202 2015.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006-291X

Access to Document (DOI)

Conformational Disorder of the Most Immature Cu, Zn-Superoxide Dismutase Leading to Amyotrophic Lateral Sclerosis

Furukawa, Yoshiaki, Anzai, Itsuki, Akiyama, Shuji, Imai, Mizue, Cruz, Fatima Joy C., Saio, Tomohide, Nagasawa, Kenichi, Nomura, Takao, Ishimori, Koichiro

JOURNAL OF BIOLOGICAL CHEMISTRY 291 ( 8 ) 4144 - 4155 2016.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 0021-9258

Access to Document (DOI)

A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43

Furukawa, Yoshiaki, Suzuki, Yoh, Fukuoka, Mami, Nagasawa, Kenichi, Nakagome, Kenta, Shimizu, Hideaki, Mukaiyama, Atsushi, Akiyama, Shuji

SCIENTIFIC REPORTS 6 4144 - 4155 2016.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 2045-2322

Access to Document (DOI)

Novel oxindole compounds inhibit the aggregation of amyloidogenic proteins associated with neurodegenerative diseases

Kimura S., Kamishina H., Hirata Y., Furuta K., Furukawa Y., Yamato O., Maeda S., Kamatari Y.O.

Biochimica et Biophysica Acta - General Subjects (Biochimica et Biophysica Acta - General Subjects) 1866 ( 5 ) 2022.05

ISSN 03044165

Amyloidogenic proteins form aggregates in cells, thereby leading to neurodegenerative disorders, including Alzheimer's and prion's disease, amyotrophic lateral sclerosis (ALS) in humans, and degenerative myelopathy (DM) and cognitive dysfunction in dogs. Hence, many small-molecule compounds have been screened to examine their inhibitory effects on amyloidogenic protein aggregation. However, no effective drug suitable for transition to clinical use has been found. Here we examined several novel oxindole compounds (GIF compounds) for their inhibitory effects on aggregate formation of the canine mutant superoxide dismutase 1 (cSOD1 E40K), a causative mutation resulting in DM, using Thioflavin-T fluorescence. Most GIF compounds inhibited the aggregation of cSOD1 E40K. Among the compounds, GIF-0854-r and GIF-0890-r were most effective. Their inhibitory effects were also observed in cSOD1 E40K-transfected cells. Additionally, GIF-0890-r effectively inhibited the aggregate formation of human SOD1 G93A, a causative mutation of ALS. GIF-0827-r and GIF-0856-r also effectively inhibited aggregate formation of human prion protein (hPrP). Subsequently, the correlation between their inhibitory effects on cSOD1 and hPrP aggregation was shown, indicating GIF compounds inhibited the aggregate formation of multiple amyloidogenic proteins. Conclusively, the novel oxindole compounds (GIF-0827-r, GIF-0854-r, GIF-0856-r, and GIF-0890-r) are proposed as useful therapeutic candidates for amyloidogenic neurodegenerative disorders.

Access to Document (DOI)

Metal distribution in Cu/Zn-superoxide dismutase revealed by native mass spectrometry

Tajiri M., Aoki H., Shintani A., Sue K., Akashi S., Furukawa Y.

Free Radical Biology and Medicine (Free Radical Biology and Medicine) 183 60 - 68 2022.04

ISSN 08915849

Cu/Zn-superoxide dismutase (SOD1) is a homodimer with two identical subunits, each of which binds a copper and zinc ion in the native state. In contrast to such a text book case, SOD1 proteins purified in vitro or even in vivo have been often reported to bind a non-stoichiometric amount of the metal ions. Nonetheless, it is difficult to probe how those metal ions are distributed in the two identical subunits. By utilizing native mass spectrometry, we showed here that addition of a sub-stoichiometric copper/zinc ion to SOD1 led to the formation of a homodimer with a stochastic combination of the subunits binding 0, 1, and even 2 metal ions. We also found that the homodimer was able to bind four copper or four zinc ions, implying the binding of a copper and zinc ion at the canonical zinc and copper site, respectively. Such ambiguity in the metal quota and selectivity could be avoided when an intra-subunit disulfide bond in SOD1 was reduced before addition of the metal ions. Apo-SOD1 in the disulfide-reduced state was monomeric and was found to bind only one zinc ion per monomer. By binding a zinc ion, the disulfide-reduced SOD1 became conformationally compact and acquired the ability to dimerize. Based upon the results in vitro, we describe the pathway in vivo enabling SOD1 to bind copper and zinc ions with high accuracy in their quota and selectivity. A failure of correct metallation in SOD1 will also be discussed in relation to amyotrophic lateral sclerosis.

Access to Document (DOI)

Stagnation of glymphatic interstitial fluid flow and delay in waste clearance in the SOD1-G93A mouse model of ALS

Hirose M., Asano M., Watanabe-Matsumoto S., Yamanaka K., Abe Y., Yasui M., Tokuda E., Furukawa Y., Misawa H.

Neuroscience Research (Neuroscience Research) 171 74 - 82 2021.10

ISSN 01680102

Overexpression and mislocalization of aquaporin-4 (AQP4) in the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS) have previously been reported. However, how alterations of AQP4 affect interstitial bulk flow in the brain and spinal cord, the so-called glymphatic system, is unclear. Here, we report an enhanced accumulation of disease-associated SOD1 species including SOD1 oligomers in SOD1G93A;AQP4−/− mice compared with SOD1G93A mice during ALS disease progression, as analyzed by sandwich ELISA. By directly injecting SOD1 oligomers into the spinal cord parenchyma, we observed a significantly larger delay in clearance of biotinylated or fluorescent-labeled SOD1 oligomers in AQP4−/− mice than in wild-type mice. Furthermore, when we injected the fluorescent-labeled tracer protein ovalbumin into the cisterna magna and analyzed the tracer distribution in the cervical spinal cord, approximately 35 % processing ability was found to be reduced in SOD1G93A mice compared to wild-type mice. These results suggest that the glymphatic system is abnormal and that waste clearance is delayed in SOD1G93A mice.

Access to Document (DOI)

A dual role of cysteine residues in the maturation of prokaryotic Cu/Zn-superoxide dismutase

Shintani A., Shintani A., Kokubo T.

Metallomics (Metallomics) 13 ( 9 ) 2021.09

ISSN 17565901

Bacterial Cu/Zn-superoxide dismutase (SodC) is an enzyme catalyzing the disproportionation of superoxide radicals, to which the binding of copper and zinc ions and the formation of an intramolecular disulfide bond are essential. We previously showed that Escherichia coli SodC (SodC)was prone to spontaneous degradation in vivo in an immature form prior to the introduction of the disulfide bond. The post-Translational maintenance involving the metal binding and the disulfide formation would thus control the stability as well as the enzymatic function of SodC; however, a mechanism of the SodC maturation remains obscure. Here, we show that the disulfide-reduced SodC can secure a copper ion as well as a zinc ion through the thiolate groups. Furthermore, the disulfide-reduced SodC was found to bind cuprous and cupric ions more tightly than SodC with the disulfide bond. The thiolate groups ligating the copper ion were then autooxidized to form the intramolecular disulfide bond, leading to the production of enzymatically active SodC. Based upon the experiments in vitro, therefore, we propose a mechanism for the activation of SodC, in which the conserved Cys residues play a dual role: The acquisition of a copper ion for the enzymatic activity and the formation of the disulfide bond for the structural stabilization.

Access to Document (DOI)

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Furukawa Y., Tokuda E.

Translational Neurodegeneration (Translational Neurodegeneration) 9 ( 1 ) 2020.08

Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons. Increasing numbers of genes are found to be associated with ALS; among those, the first identified gene, SOD1 coding a Cu/Zn-superoxide dismutase protein (SOD1), has been regarded as the gold standard in the research on a pathomechanism of ALS. Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1 (SOD1-ALS). Nonetheless, involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations (non-SOD1 ALS), which occupies more than 90% of total ALS cases. In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins; therefore, SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases, non-SOD1 ALS. In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo, we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.

Access to Document (DOI)

Oxidative misfolding of Cu/Zn-superoxide dismutase triggered by non-canonical intramolecular disulfide formation

Anzai I., Tokuda E., Handa S., Misawa H., Akiyama S., Furukawa Y.

Free Radical Biology and Medicine (Free Radical Biology and Medicine) 147 187 - 199 2020.02

ISSN 08915849

© 2019 Elsevier Inc. Misfolded Cu/Zn-superoxide dismutase (SOD1) is a pathological species in a subset of amyotrophic lateral sclerosis (ALS). Oxidative stress is known to increase in affected spinal cords of ALS and is thus considered to cause damages on SOD1 leading to the misfolding and aggregation. Despite this, it still remains elusive what triggers misfolding of SOD1 under oxidizing environment. Here, we show that a thiol group of Cys111 in SOD1 is oxidized to a sulfenic acid with hydrogen peroxide and reveal that further dissociation of the bound metal ions from the oxidized SOD1 allows another free Cys residue (Cys6) to nucleophilically attack the sulfenylated Cys111. As a result, an intra-molecular disulfide bond forms between Cys6 and Cys111. Such an abnormal SOD1 with the non-canonical disulfide bond was conformationally extended with significant cytotoxicity as well as high propensity to aggregate. Taken together, we propose a new model of SOD1 misfolding under oxidizing environment, in which formation of the non-canonical intramolecular disulfide bond plays a pivotal role.

Access to Document (DOI)

Wild-type Cu/Zn-superoxide dismutase is misfolded in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis

Tokuda E., Takei Y.I., Ohara S., Fujiwara N., Hozumi I., Furukawa Y.

Molecular Neurodegeneration (Molecular Neurodegeneration) 14 ( 1 ) 2019.11

© 2019 The Author(s). Background: A subset of familial forms of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene coding Cu/Zn-superoxide dismutase (SOD1). Mutant SOD1 proteins are susceptible to misfolding and abnormally accumulated in spinal cord, which is most severely affected in ALS. It, however, remains quite controversial whether misfolding of wild-type SOD1 is involved in more prevalent sporadic ALS (sALS) cases without SOD1 mutations. Methods: Cerebrospinal fluid (CSF) from patients including sALS as well as several other neurodegenerative diseases and non-neurodegenerative diseases was examined with an immunoprecipitation assay and a sandwich ELISA using antibodies specifically recognizing misfolded SOD1. Results: We found that wild-type SOD1 was misfolded in CSF from all sALS cases examined in this study. The misfolded SOD1 was also detected in CSF from a subset of Parkinson's disease and progressive supranuclear palsy, albeit with smaller amounts than those in sALS. Furthermore, the CSF samples containing the misfolded SOD1 exhibited significant toxicity toward motor neuron-like NSC-34 cells, which was ameliorated by removal of the misfolded wild-type SOD1 with immunoprecipitation. Conclusions: Taken together, we propose that misfolding of wild-type SOD1 in CSF is a common pathological process of ALS cases regardless of SOD1 mutations.

Access to Document (DOI)

Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein

Tanaka G., Yamanaka T., Furukawa Y., Kajimura N., Mitsuoka K., Nukina N.

Biochimica et Biophysica Acta - Molecular Basis of Disease (Biochimica et Biophysica Acta - Molecular Basis of Disease) 1865 ( 6 ) 1410 - 1420 2019.06

ISSN 09254439

© 2019 Elsevier B.V. Synucleinopathies comprise a diverse group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. These share a common pathological feature, the deposition of alpha-synuclein (a-syn) in neurons or oligodendroglia. A-syn is highly conserved in vertebrates, but the primary sequence of mouse a-syn differs from that of human at seven positions. However, structural differences of their aggregates remain to be fully characterized. In this study, we found that human and mouse a-syn aggregated in vitro formed morphologically distinct amyloid fibrils exhibiting twisted and straight structures, respectively. Furthermore, we identified different protease-resistant core regions, long and short, in human and mouse a-syn aggregates. Interestingly, among the seven unconserved amino acids, only A53T substitution, one of the familial PD mutations, was responsible for structural conversion to the straight-type. Finally, we checked whether the structural differences are transmissible by seeding and found that human a-syn seeded with A53T aggregates formed straight-type fibrils with short protease-resistant cores. These results suggest that a-syn aggregates form sequence-dependent polymorphic fibrils upon spontaneous aggregation but become seed structure-dependent upon seeding.

Access to Document (DOI)

Biochemical and morphological classification of disease-associated alpha-synuclein mutants aggregates

Tanaka G., Yamanaka T., Furukawa Y., Kajimura N., Mitsuoka K., Nukina N.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 508 ( 3 ) 729 - 734 2019.01

ISSN 0006291X

© 2018 Elsevier Inc. Alpha-synuclein (a-syn) aggregation in brain is implicated in several synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Until date, at least six disease-associated mutations in a-syn (namely A30P, E46K, H50Q, G51D, A53T, and A53E) are known to cause dominantly inherited familial forms of synucleinopathies. Previous studies using recombinant proteins have reported that a subset of disease-associated mutants show higher aggregation propensities and form spectroscopically distinguishable aggregates compared to wild-type (WT). However, morphological and biochemical comparison of the aggregates for all disease-associated a-syn mutants have not yet been performed. In this study, we performed electron microscopic examination, guanidinium hydrochloride (GdnHCl) denaturation, and protease digestion to classify the aggregates from their respective point mutations. Using electron microscopy we observed variations of amyloid fibrillar morphologies among the aggregates of a-syn mutants, mainly categorized into two groups: twisted fibrils observed for both WT and E46K while straight fibrils for the other mutants. GdnHCl denaturation experiments revealed the a-syn mutants except for E46K were more resistant than WT against the denaturation. Mass spectrometry analysis of protease-treated aggregates showed a variety of protease-resistant cores, which may correspond to their morphological properties. The difference of their properties could be implicated in the clinicopathological difference of synucleinopathies with those mutations.

Access to Document (DOI)

Prion-like properties of misfolded Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis: Update and perspectives

Tokuda E., Marklund S., Furukawa Y.

Yakugaku Zasshi (Yakugaku Zasshi) 139 ( 7 ) 1015 - 1019 2019

ISSN 00316903

© 2019 The Pharmaceutical Society of Japan. Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that is characterized by the loss of motor neurons, which results in progressive muscle atrophy. The pathology spreads from the initial site of onset to contiguous anatomic regions. Mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) have been identified in a dominantly inherited form of ALS (ALS-SOD1). A major hallmark of ALS-SOD1 is the abnormal accumulation of conformationally aberrant SOD1 protein (i.e., misfolded SOD1) within motor neurons. Emerging experimental evidence has suggested that misfolded proteins associated with neurodegenerative diseases exhibit prion-like properties, i.e., misfolded proteins act as conformational templates that convert normal proteins into a pathogenic form. Possibly as a result of this prion-like self-propagation property, misfolded forms of pathological proteins are considered to accumulate in the central nervous system and cause neurodegeneration. In this article, we review recent evidence for the role of prion-like mechanisms in ALS-SOD1. In particular, we discuss the propensity of misfolded SOD1 to act as a pathological seed, spread between cells, and propagate neuroanatomically.

Access to Document (DOI)

Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-specific intrabody with dual proteolytic signals

Tamaki Y., Shodai A., Morimura T., Hikiami R., Minamiyama S., Ayaki T., Tooyama I., Furukawa Y., Takahashi R., Urushitani M.

Scientific Reports (Scientific Reports) 8 ( 1 ) 2018.12

© 2018 The Author(s). Aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is implicated in the pathogenesis of sporadic and certain familial forms of amyotrophic lateral sclerosis (ALS), suggesting elimination of TDP-43 aggregates as a possible therapeutic strategy. Here we generated and investigated a single-chain variable fragment (scFv) derived from the 3B12A monoclonal antibody (MAb) that recognises D247 of the TDP-43 nuclear export signal, an epitope masked in the physiological state. In transfected HEK293A cells, 3B12A scFv recapitulated the affinity of the full-length MAb to mislocalised TDP-43 with a defective nuclear localising signal and to a TDP-43 inclusion mimic with cysteine-to-serine substitution at RRM1. Moreover, 3B12A scFv accelerated proteasome-mediated degradation of aggregated TDP-43, likely due to an endogenous PEST-like proteolytic signal sequence in the VH domain CDR2 region. Addition of the chaperone-mediated autophagy (CMA)-related signal to 3B12A scFv induced HSP70 transcription, further enhancing TDP-43 aggregate clearance and cell viability. The 3B12A scFv also reduced TDP-43 aggregates in embryonic mouse brain following in utero electroporation while causing no overt postnatal brain pathology or developmental anomalies. These results suggest that a misfolding-specific intrabody prone to synergistic proteolysis by proteasomal and autophagic pathways is a promising strategy for mitigation of TDP-43 proteinopathy in ALS.

Access to Document (DOI)

Cu/Zn-superoxide dismutase forms fibrillar hydrogels in a pH-dependent manner via a water-rich extended intermediate state

Fujiwara N., Wagatsuma M., Oba N., Yoshihara D., Tokuda E., Sakiyama H., Eguchi H., Ichihashi M., Furukawa Y., Inoue T., Suzuki K.

PLoS ONE (PLoS ONE) 13 ( 10 ) 2018.10

© 2018 Fujiwara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Under certain conditions, amyloid-like fibrils can develop into three-dimensional networks and form hydrogels by a self-assembly process. When Cu/Zn superoxide dismutase (SOD1), an anti-oxidative enzyme, undergoes misfolding, fibrillar aggregates are formed, which are a hallmark of a certain form of familial amyotrophic lateral sclerosis (ALS). However, the issue of whether SOD1 fibrils can be assembled into hydrogels remains to be tested. Here, we show that the SOD1 polypeptides undergo hydrogelation accompanied by the formation of thioflavin T-positive fibrils at pH 3.0 and 4.0, but not at pH 5.0 where precipitates are formed. The results of viscoelastic analyses indicate that the properties of SOD1 hydrogels (2%) were similar to and slightly more fragile than a 0.25% agarose gel. In addition, monitoring by a quartz crystal microbalance with admittance analysis showed that the denaturing of immobilized SOD1 on a sensor under the hydrogelation conditions at pH 3.0 and 4.0 resulted in an increase in the effective acoustic thickness from ~3.3 nm (a folded rigid form) to ~50 and ~100 nm (an extended water-rich state), respectively. In contrast, when SOD1 was denatured under the same conditions at pH 5.0, a compact water-poor state with an effective acoustic thickness of ~10 nm was formed. The addition of physiological concentrations of NaCl to the pH 4.0 sample induced a further extension of the SOD1 with larger amounts of water molecules (with an effective acoustic thickness of ~200 nm) but suppressed hydrogel formation. These results suggest that different denatured intermediate states of the protein before self-assembly play a major role in determining the characteristics of the resulting aggregates and that a conformational change to a suitable level of extended water-rich intermediate state before and/or during intermolecular assembling is required for fibrillation and hydrogelation in the case of globular proteins.

Access to Document (DOI)

Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment

Okuzumi A., Kurosawa M., Hatano T., Takanashi M., Nojiri S., Fukuhara T., Yamanaka T., Miyazaki H., Yoshinaga S., Furukawa Y., Shimogori T., Hattori N., Nukina N.

Acta neuropathologica communications (Acta neuropathologica communications) 6 ( 1 ) 2018.09

Accumulating evidence suggests that the lesions of Parkinson's disease (PD) expand due to transneuronal spreading of fibrils composed of misfolded alpha-synuclein (a-syn), over the course of 5-10 years. However, the precise mechanisms and the processes underlying the spread of these fibril seeds have not been clarified in vivo. Here, we investigated the speed of a-syn transmission, which has not been a focus of previous a-syn transmission experiments, and whether a-syn pathologies spread in a neural circuit-dependent manner in the mouse brain. We injected a-syn preformed fibrils (PFFs), which are seeds for the propagation of a-syn deposits, either before or after callosotomy, to disconnect bilateral hemispheric connections. In mice that underwent callosotomy before the injection, the propagation of a-syn pathology to the contralateral hemisphere was clearly reduced. In contrast, mice that underwent callosotomy 24 h after a-syn PFFs injection showed a-syn pathology similar to that seen in mice without callosotomy. These results suggest that a-syn seeds are rapidly disseminated through neuronal circuits immediately after seed injection, in a prion-like seeding experiment in vivo, although it is believed that clinical a-syn pathologies take years to spread throughout the brain. In addition, we found that botulinum toxin B blocked the transsynaptic transmission of a-syn seeds by specifically inactivating the synaptic vesicle fusion machinery. This study offers a novel concept regarding a-syn propagation, based on the Braak hypothesis, and also cautions that experimental transmission systems may be examining a unique type of transmission, which differs from the clinical disease state.

Access to Document (DOI)

Identification of a novel zinc-binding protein, C1orf123, as an interactor with a heavy metalassociated domain

Furukawa Y., Lim C., Tosha T., Yoshida K., Hagai T., Akiyama S., Watanabe S., Nakagome K., Shiro Y.

PLoS ONE (PLoS ONE) 13 ( 9 ) 2018.09

© 2018 Furukawa et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Heavy metal-associated (HMA) domains bind metal ions at its Cys-x-x-Cys (CxxC) motif and constitute an intracellular network for trafficking of metal ions for utilization and detoxification. We thus expect that novel metalloproteins can be identified by screening proteins interacting with a HMA domain. In this study, we performed yeast two-hybrid screening of the human proteome and found an uncharacterized protein encoded as open reading frame 123 in chromosome 1 (C1orf123) that can interact specifically with the HMA domain of a copper chaperone for superoxide dismutase (CCSdI). Our X-ray structural analysis of C1orf123 further revealed that it binds a Zn 2+ ion in a tetrahedral coordination with four thiolate groups from two conserved CxxC motifs. For the interaction between C1orf123 and CCSdI, the CxxC motifs in both C1orf123 and CCSdI were required, implying metal-mediated interaction through the CxxC motifs. Notably, C1orf123 did not interact with several other HMA domains containing CxxC motifs, supporting high specificity in the interaction between C1orf123 and CCSdI. Based upon these results, we further discuss functional and structural significance of the interaction between C1orf123 and CCS.

Access to Document (DOI)

A copper-deficient form of mutant Cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis

Tokuda E., Nomura T., Ohara S., Watanabe S., Yamanaka K., Morisaki Y., Misawa H., Furukawa Y.

Biochimica et Biophysica Acta - Molecular Basis of Disease (Biochimica et Biophysica Acta - Molecular Basis of Disease) 1864 ( 6 ) 2119 - 2130 2018.06

ISSN 09254439

© 2018 Elsevier B.V. Dominant mutations in the gene encoding copper and zinc-binding superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS). Abnormal accumulation of misfolded SOD1 proteins in spinal motoneurons is a major pathological hallmark in SOD1-related ALS. Dissociation of copper and/or zinc ions from SOD1 has been shown to trigger the protein aggregation/oligomerization in vitro, but the pathological contribution of such metal dissociation to the SOD1 misfolding still remains obscure. Here, we tested the relevance of the metal-deficient SOD1 in the misfolding in vivo by developing a novel antibody (anti-apoSOD), which exclusively recognized mutant SOD1 deficient in metal ions at its copper-binding site. Notably, anti-apoSOD-reactive species were detected specifically in the spinal cords of the ALS model mice only at their early pre-symptomatic stages but not at the end stage of the disease. The cerebrospinal fluid as well as the spinal cord homogenate of one SOD1-ALS patient also contained the anti-apoSOD-reactive species. Our results thus suggest that metal-deficiency in mutant SOD1 at its copper-binding site is one of the earliest pathological features in SOD1-ALS.

Access to Document (DOI)

Pathological roles of copper dynamics in amyotrophic lateral sclerosis

Furukawa Y.

Seikagaku (Seikagaku) 90 ( 3 ) 311 - 319 2018

ISSN 00371017

Access to Document (DOI)

Immunochemical characterization on pathological oligomers of mutant Cu/Znsuperoxide dismutase in amyotrophic lateral sclerosis

Tokuda, Eiichi, Anzai, Itsuki, Nomura, Takao, Toichi, Keisuke, Watanabe, Masahiko, Ohara, Shinji, Watanabe, Seiji, Yamanaka, Koji, Morisaki, Yuta, Misawa, Hidemi, Furukawa, Yoshiaki

MOLECULAR NEURODEGENERATION 12 2017.01

Research paper (scientific journal), Accepted, ISSN 1750-1326

Access to Document (DOI)

Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Tokuda, Eiichi, Furukawa, Yoshiaki

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 17 ( 5 ) 847 - 867 2016.05

Research paper (scientific journal), ISSN 1422-0067

Access to Document (DOI)

Conformational Disorder of the Most Immature Cu, Zn-Superoxide Dismutase Leading to Amyotrophic Lateral Sclerosis

Furukawa, Yoshiaki, Anzai, Itsuki, Akiyama, Shuji, Imai, Mizue, Cruz, Fatima Joy C., Saio, Tomohide, Nagasawa, Kenichi, Nomura, Takao, Ishimori, Koichiro

JOURNAL OF BIOLOGICAL CHEMISTRY 291 ( 8 ) 4144 - 4155 2016.02

Research paper (scientific journal), ISSN 0021-9258

Access to Document (DOI)

A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43

Furukawa, Yoshiaki, Suzuki, Yoh, Fukuoka, Mami, Nagasawa, Kenichi, Nakagome, Kenta, Shimizu, Hideaki, Mukaiyama, Atsushi, Akiyama, Shuji

SCIENTIFIC REPORTS 6 4144 - 4155 2016.02

Research paper (scientific journal), ISSN 2045-2322

Access to Document (DOI)

　 Previous page - Next page 　