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2015-02-28: The winter meeting of the Synapse Pathology research group was held at Shikinoyu Goura Seiunsou, between February 28 – March 1, 2015. (Click here for the photo gallery from the event.)
2015-01-29: “Press Release”
The research group led by Dr. Yukio Kawahara clarified the biological significance of the fragmentation of TDP-43, a neurodegeneration-associated protein. TDP-43 and its C-terminal fragment of 25 kDa (CTF25) play critical roles in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although overexpression of TDP-43 in cultured cells and animals results in the production of CTF25, the cleavage site that generates CTF25 and biological significance of the cleavage remain undetermined. In this study, we identify Asp174 as a predominant cleavage site for CTF25. TDP-43 is cleaved initially after Asp174, which activates caspase-3/7 to accelerate TDP-43 fragmentation. Consequently, blockage of this cleavage results in a severe delay in TDP-43 clearance and prolonged necrotic cell death. We further show that endoplasmic reticulum membrane-bound caspase-4 is the enzyme responsible for the cleavage after Asp174 and inhibition of caspase-4 activity slows TDP-43 fragmentation and reduces cell viability. These findings suggest that caspase-4-mediated cleavage after Asp174 is an initiator of TDP-43 clearance, which is required to avoid cell death induced by overexpressed TDP-43. These results have been published in Nature Communications. (Click here for details.)
2014-12-19: “Press Release”
Mikio Hoshino (Director of Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry) and colleagues clarified the molecular and physiological function for AUTS2 (Autism Susceptibility Candidate 2) gene that has been associated with various psychiatric disorders, such as autism spectrum disorders, schizophrenia, ADHD, drug addiction, and epilepsy. Hoshino and his colleagues revealed that AUTS2 in cytoplasm upregulates and downregulates Rac1 and Cdc42, respectively, to reorganize actin cytoskeleton in neurons, which is required for proper neuronal migration and neurite extension/branching. This work may give insights into understanding human psychiatric disorders caused by AUTS mutations. These results have been published in Cell Reports. (Click here for details. [in Japanese])
2014-12-18: “Press Release”
Yasunori Hayashi, MD PhD (RIKEN Brain Science Institute and Saitama University) and his collaborators in RIKEN, Yokohama City University Graduate School of Medicine, and Yamaguchi University Graduate School of Medicine, reported a finding that forces us to revise a well-accepted theory of molecular mechanism of learning and memory. Information transmission of between two neurons is carried out in a tiny cellular structure called “synapse”. There, glutamate (the main component of MSG) and its receptor (glutamate receptor) serve as essential chemical messenger. It has been widely accepted that learning induces phosphorylation of the glutamate receptor, which changes the transmission efficacy and that this mechanism plays an important role in memory. But this scheme has not been fully proven because it has been difficult to quantify the proportion of phosphorylated protein. Dr. Hayashi and colleagues used a novel method called Phos-tag SDS-PAGE, invented by Dr. Kinoshita in Hiroshima University, to solve this issue. As a result, they demonstrated that the amount of phosphorylated receptor is at a negligible level, which is contradictory to the accepted model. They proposed new models that might explain their findings as well as emphasized the importance of actually quantifying the stoichiometry of protein phosphorylation. This result was published in online version of Neuron on Dec. 18, 2014.
2014-12-13: A joint symposium of the Synapse Pathology research group was held in The winter symposium of the Comprehensive Brain Science Network at TOKYO GARDEN PALACE on December 13, 2014. (click here to see program [in Japanese]).
2014-12-11: A joint symposium of the Synapse Pathology research group was held in The winter symposium of the Comprehensive Brain Science Network at the M&D tower TMDU on December 11, 2014. (click here to see program [in Japanese]).
2014-12-08: “Press Release”
This press release, issued by National Institute for Physiological Sciences (NIPS), outlines the findings of the Publicly Invited Research Group, Yuko Fukata (Associate Professor, NIPS). The group found that the conformational defect in LGI1 protein causes autosomal dominant lateral temporal lobe epilepsy (ADLTE) which is a form of familial epilepsy. They showed that treatment with a chemical corrector called “chemical chaperone” ameliorates increased seizure susceptibility in a mouse model of human epilepsy by correcting the conformational defect of the mutated LGI1 protein. This was published in Nature Medicine (December 8, 2014 electronic edition)(Click here for details. [in Japanese])
2014-11-21: “Press Release”
Voltage-gated Na⁺ channel β subunits are multifunctional molecules that modulate Na⁺ channel activity and regulate cell adhesion, migration and neurite outgrowth. β subunits including β4 are known to be highly concentrated in the nodes of Ranvier and axon initial segments in myelinated axons. The research group led by Dr. Nobuyuki Nukina shows diffuse β4 localization in striatal projection fibers using transgenic mice that express fluorescent protein in those fibers. These axons are unmyelinated, forming large, inhibitory fiber bundles. Furthermore, the group reports β4 dimer expression in mouse brain, with high levels of β4 dimers in the striatal projection fascicles, suggesting a specific role of β4 in those fibers. Scn4b-deficient mice show a resurgent Na⁺ current reduction, decreased repetitive firing frequency in medium spiny neurons and increased failure rates of inhibitory postsynaptic currents evoked with repetitive stimulation, indicating an in vivo channel regulatory role of β4 in the striatum. These results have been published in Nature Communications.(Click here for details. [in Japanese])
2014-10-14: “Press Release”
The motoneural control of skeletal muscle contraction requires the neuromuscular junction (NMJ), a synapse between the motor nerve and myotube. Yuji Yamanashi (Inst. Med. Sci. Univ. Tokyo) and his colleagues had previously found that the muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation (Science, 312:1802-05, 2006; Science Signal., 2:ra7, 2009). Interestingly, there is another MuSK activator, motor neuron-derived agrin. In this study, they demonstrated that forced expression of Dok-7 in muscle enhanced MuSK activation in mice lacking agrin and restored embryonic formation, but not postnatal maintenance, of NMJs, demonstrating that agrin plays an essential role distinct from MuSK activation in the postnatal maintenance of NMJs. The paper appeared in Proc. Natl. Acad. Sci. USA on November 18.(Click here for details. [in Japanese])
2014-10-09: “Press Release”
p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. The research group led by Dr.Nobuyuki Nukina investigated the effect of p62 depletion in HD model mice. Loss of p62 in these models led to longer life spans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyQ length. The results suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions. The paper has been published in Hum Mol Genet.
2014-09-30: “Press Release”
The research group led by Dr.Nobuyuki Nukina revealed that the RNA-binding protein muscleblind-like 1 (MBNL1) promoted nuclear accumulation of mutant RNA containing a CUG or CAG repeat, some of which produced proteins containing homopolymeric tracts such as polyglutamine. Furthermore, MBNL1 repressed the expression of these homopolymeric proteins including those presumably produced through repeat-associated non-ATG (RAN) translation. These results suggest that nuclear retention of expanded RNA reflects a novel role of MBNL proteins in repressing aberrant protein expression and may provide pathological and therapeutic implications for a wide range of repeat expansion diseases associated with nuclear RNA retention and/or RAN translation. The paper has been published in Human Molecular Genetics.
2014-09-19: “Press Release”
The neuromuscular junction (NMJ) is the synapse between a motor neuron and skeletal muscle. Yuji Yamanashi (Inst. Med. Sci. Univ. Tokyo) and his colleagues had previously found that the muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs (Science, 312:1802-05, 2006; Science, 313:1975-78, 2006; Science Signal., 2:ra7, 2009). In this study, they used an adeno-associated virus vector to deliver DOK7 to enlarge the neuromuscular junction. This therapy improved motor activity and life span of mouse models of two distinct neuromuscular disorders with small NMJs. The paper appeared in Science on September 19. (Click here for details. [in Japanese])
2014-09-17: “Press Release”
The research group led by the Principal Investigator of the Foundation of Synapse and Neurocircuit Pathology project, Hitoshi Okazawa (Professor, Medical Research Institute, Director, Center for Brain Integrative Research, Tokyo Medical and Dental University) elucidated molecular basis for the earliest synapse pathology in preclinical Alzheimer’s disease (AD) brain. In this study, the research group performed comprehensive phosphoprotein analysis with brain samples from AD patients and four mouse models by using high-end mass spectrometry, and analyzed the data by methods of systems biology using a super computer. They found that 17 phosphoproteins related to synapse functions are changed in the brains of mouse AD models and human AD patients. Especially, the change of MARCKS started at a preclinical stage even before histological Aβ deposition. Two-photon microscopic observation revealed recovery of abnormal spine formation in the AD model mice by targeting MARCKS or by inhibiting its candidate kinases. This study proposed a novel strategy of AD treatment which targets the earliest pathology. These results have been published online in Human Molecular Genetics. (Click here for details. [in Japanese])
2014-08-28: “Press Release”
The research group led by Dr. Masahisa Katsuno (Nagoya University Graduate School of Medicine) clarified the therapeutic effects of pioglitazone on spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease caused by the expansion of a CAG trinucleotide repeat in the androgen receptor gene. The group showed that the expression levels of peroxisome proliferator-activated receptor-γ (PPARγ), a key regulator of mitochondrial biogenesis, were decreased in mouse and cellular models of SBMA and in tissues from SBMA patients. Treatment with pioglitazone improved the viability of SBMA cellular and mouse models. Furthermore, the administration of PG suppressed mitochondrial dysfunction, oxidative stress, nuclear factor-κB (NFκB) signal activation and inflammation both in the spinal cords and skeletal muscles of the SBMA mice. The results of the present study suggest that pioglitazone has direct effects on both neuronal and muscular degeneration in SBMA. The activation of NFκB plays an essential role in the neuromuscular degeneration in SBMA, and skeletal muscle is an important target for therapies that alleviate neuromuscular symptoms of SBMA. These results have been published in Human Molecular Genetics.
2014-07-29: “Press Release”
The research group led by the Principal Investigator of the Foundation of Synapse and Neurocircuit Pathology project, Hitoshi Okazawa (Professor, Medical Research Institute, Director, Center for Brain Integrative Research, Tokyo Medical and Dental University) elucidated a molecular pathomechanism of microcephaly by mutations of PQBP1 (polyglutamine binding protein-1) gene, which is known as a major causative gene for microcephaly. In this study the research group made a conditional KO mouse which does not express PQBP1 in neural stem progenitor cells (NSPCs). The mouse model showed microcephaly without structural change (primary microcephaly) and a cell cycle time elongation in NSPCs, which is basically mediated by transcription/splicing abnormalities including a number of genes related to the cell cycle regulation such as APC2 and APC4. The mice did not showed accelerated production of neurons, increased cell death of NSPCs, or abnormal migration. They confirmed supplementation of APC4 recovered the cell cycle time elongation and NSPCs expansion. Moreover, the research group performed peritoneal injection of adeno-associated virus (AAV) vector into pregnant mice to express PQBP1 in embryos, and confirmed recovery of the microcephaly and behavioral abnormalities of offsprings. This study proposed a new mechanism of primary microcephaly and a treatment strategy. These results have been published online in Molecular Psychiatry. (Click here for details. [in Japanese])
2014-07-23: “Press Release”
Researchers lead by Professor Takeshi Iwatsubo, M.D., Ph.D. at the University of Tokyo, identified the molecular mechanistic action of phenylimidazole-type γ-secretase modulators that have been developed as therapeutics against Alzheimer disease. These compounds activate the proteolytic activity of γ-secretase by targeting to the extracellular region of presenilin, an enzymatic subunit of γ-secretase, to allosterically induce conformational changes at the catalytic site. These findings would lead to the rational design of γ-secretase modulators with better potency based on the structure and function of the molecule, and its interaction with the target, and the discovery of effective therapeutics against Alzheimer disease. These results have been published in Proc. Natl. Acad. Sci. USA. (Click here for details.)
2014-07-23: “Press Release”
The transmembrane protein Elfn1 is implicated in synaptic plasticity. Jun Aruga (Nagasaki Univ. Grad. Sch. Biomedical Sciences) and his colleagues identified ELFN1 mutations in epilepsy and attention-deficit hyperactivity disorder (ADHD) patients, and show that loss of Elfn1 in mice results in seizures, ADHD-like behaviour and impaired recruitment of mGluR7, a novel binding partner identified in this study. The paper appeared in Nature Communications on July 22. (Click here for details. [in Japanese])
2014-06-27: “Press Release”
This press release, issued by Kyoto University, outlines the results of collaborative research conducted by a Planned Research team member, Haruhisa Inoue (Professor, Center for iPS Cell Research and Application, Kyoto University). The authors showed that transplantation of human iPS cell-derived glial-rich neural progenitors to spinal cord of ALS model mice attenuated motor neuron degeneration. These results demonstrate the efficacy of cell therapy for ALS by the use of human iPS cells as a cell source, and were published in the journal Stem Cell Reports. (Click here for details. [in Japanese])
2014-06-19: “Press Release”
The research group led by Dr. Yukio Kawahara clarified the physiological function of Ataxin-2, a neurodegeneration-associated protein. Abnormal expansion of polyglutamine (polyQ) stretch in Ataxin-2 leads to spinocerebellar ataxia type 2, whereas intermediate polyQ expansion is associated with risk for ALS. However, the physiological role of Ataxin-2 as well as the pathological significance of polyQ expansion remains unknown. In this study, we found that Ataxin-2 binds directly to RNAs. High-throughput sequencing of Ataxin-2-bound RNAs prepared by PAR-CLIP revealed that Ataxin-2 binds predominantly to uridine-rich elements, including well-characterized cis-regulatory AU-rich elements, in the 3'UTRs of target mRNAs. We further found that Ataxin-2 stabilizes target mRNAs and disease-associated polyglutamine expansion downregulates the physiological activity of Ataxin-2. These findings suggest that Ataxin-2 is an RNA-binding protein that targets cis-regulatory elements in 3'UTRs to stabilize a subset of mRNAs. These results have been published in Molecular Cell. (Click here for details. [in Japanese])
2014-04-30: “Press Release”
The research group led by the Principal Investigator of the Foundation of Synapse and Neurocircuit Pathology project, Hitoshi Okazawa (Professor, Medical Research Institute, Tokyo Medical and Dental University) elucidated a molecular pathomechanism of intellectual disability by PQBP1 (polyglutamine binding protein-1) mutations. PQBP1 is known as a major causative gene for intellectual disability and as a mediator of neurodegeneration. In this study the research group determined the molecular structure of PQBP1 by X-ray crystal structure analysis and discovered that YxxPxxVL motif, which is deficient in all reported cases of patients who have intellectual disability, is essential for interaction with a splicing factor U5-15kD. Therefore, it is strongly suggested that impaired RNA splicing mediated by PQBP1 mutations leads to disturbed expression of multiple genes and finally causes intellectual disability. The similar mechanism could be possible in other types of intellectual disability. These results have been published online in Nature Communications. (Click here for details. [in Japanese] )
2014-04-30: “Press Release”
The research group led by Dr. Hideyuki Okano, Dr. Yohei Okada, and Dr. Yuko Numasawa (Keio University) established induced pluripotent stem cells (iPSCs) from two patients of Pelizeus Merzbacher Disease (PMD), one of the congenital dysmyelinating neurological disorders. The research group differentiated patient-derived iPSCs into oligodendrocytes, and demonstrated successful in vitro modeling of PMD pathogenesis, such as susceptibility to ER stress and dysmyelination. The phenotypes observed in the oligodendrocytes derived from two PMD patient-iPSCs were well correlated with the clinical severity of each patient, indicating the usefulness of iPSC-derived oligodendrocytes as an in vitro model for dysmyelinating neurological disorders. These results have been published online in “Stem Cell Reports”. (Click here for details. [in Japanese])
2014-04-16: “Press Release”
The laboratory led by Yasunori Hayashi at RIKEN-Brain Science Institute and Saitama University, Brain Science Institute, in collaboration with researchers at the Picower Institute for Learning and Memory, Department of Brain and Cognitive Science, MIT, uncovered key aspects of the molecular mechanisms of learning and memory at the level of individual synapses. In a paper published in “Neuron” (Bosch et al., April 16, 2014), the authors describe how the intracellular structures that form the dendritic spine are reorganized in space and time when a single synapse is strengthened for long-term. They found that the postsynaptic components increase in specific temporal sequence. The first component which increases at synapse within a few minutes are actin and actin related protein. These proteins work together to enlarge the dendritic spine structure. Subsequently, “scaffolding proteins” in the postsynaptic density increase after one hour to consolidate the enlarged structure, dependending on the synthesis of new proteins. This sequence of increase indicates the causal relationship of the reorganization. In addition, they described the unique dynamics of the actin-binding protein cofilin, which persistently tags the potentiated synapse by binding to actin filaments and plays a critical role in consolidating spine growth.
2014-04-02: “Press Release”
Mikio Hoshino (Director of Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry) and colleagues clarified the molecular machinery for producing distinct neuronal types by regulating "spatial identities" of neural progenitors. By analyzing genetically engineered mice, the authors found that transcription factors, Ptf1a and Atoh1, confer "spatial identities" on cerebellar neural progenitors to generate inhibitory and excitatory neurons, respectively. Together with our recent findings on the regulation of temporal identities (Nature Communications, 5, 3337, 2014), this work contributes to understanding the machinery to produce various neurons. These results have been published in Journal of Neuroscience. (Click here for details. [in Japanese] )
2014-03-16, 17: International Symposium “New Frontier of Molecular Neuropathology 2014” co-sponsored Scientific Reaearch on Innovative Areas, Synapse pathology and CREST Nukina team was held at Tokyo Medical and Dental University on March 16-17, 2014. (Click here for the website of the Symposium.) (Click here for the photo gallery from the event.)
2014-03-06: “Press Release”
Mikio Hoshino (Director of Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry) and colleagues clarified the molecular machinery for producing distinct neuronal types by regulating "temporal identities" of neural progenitors. Using genetically engineered mice, the authors found cerebellar GABAergic neuron progenitors change their identities from "Purkinje cell producing type" to "interneuron producing type" during development. This temporal identity transition of GABAergic neuron progenitors are accelerated and decelerated by transcription factors, Gsx1 and Olig2, respectively, contributing to producing proper number of distinct types of neurons. These results have been published in Nature Communications. (Click here for details. [in Japanese])
2014-02-28: “Press Release”
The research group led by Dr. Takeshi Iwatsubo clarified the role of CALM protein in Alzheimer disease (AD). AD is a neurodegenerative disorder that is characterized by a massive deposition of amyloid-β protein (Aβ) as senile plaques. C-terminal length of Aβ shows a heterogeneity, which is determined by γ-secretase. Aβ42 aggregates rapidly and is thought to be a real culprit molecule for AD. Recent genetic studies suggest that a SNP near PICALM gene that encodes CALM protein is associated with the decreased risk for the onset of AD. In this study, we found that CALM impacts on Ab42 production through the modulation of endocytosis and subcellular localization of γ-secretase. This result unveils, for the first time, the pathological functions of CALM in in vitro and in vivo. These results have been published in Nature Communications. (Click here for details. [in Japanese])
2014-02-25: “Press Release”
The research group led by Dr. Nobuyuki Nukina revealed that neuronal inactivation of NF-Y transcription factor induced progressive neurodegeneration in mouse brain. Interestingly, the degeneration accompanied accumulation of ubiquitin and p62 around endoplasmic reticulum (ER) together with insoluble membrane proteins. In addition, ribosome-free ER is aberrantly increased in the perinuclear region, without inducing ER stress response. The group proposes that NF-Y is involved in a unique regulation mechanism of ER organization in mature neurons and its disruption causes previously undescribed novel neuropathology accompanying abnormal ubiquitin/p62 accumulation. These results have been published online in "Nature Communications". (Click here for details. [in Japanese])
2014-02-15: “Press Release”
The research group led by Takami Tomiyama (Associate Professor, Osaka City University) has succeeded to develop a new mouse model of Alzheimer’s disease that shows neurofibrillary tangles (NFTs) in the absence of tau mutations. The mice, which express both human APP with the Osaka mutation and wild-type human tau, exhibited Aβ oligomer accumulation, synapse loss, memory impairment at 6 months and NFT formation, neuronal loss at 18 months. The findings suggest that Aβ and human tau synergistically interact to accelerate each other’s pathology, that the presence of human tau is critical for NFT formation, and that Aβ oligomers can induce NFTs in the absence of amyloid plaques. These results have been published online in Acta Neuropathologica. (Click here for details. [in Japanese])
2013-12-22: The winter meeting of the Synapse Pathology research group was held at KKR Kamakura Wakamiya, between December 21-22, 2013. (Click here for the photo gallery from the meeting.)
2013-11-13: “Press Release”
This press release, issued by National Institute for Physiological Sciences (NIPS), outlines the findings of the Publicly Invited Research Group, Yuko Fukata (Associate Professor, NIPS). The group found that autoantibodies to LGI1, an epilepsy-related gene product, are solely associated with specific clinical features of autoimmune limbic encephalitis, seizures and memory impairment. The group also discovered the pathogenic mechanism of the antibody. This paper has been published in Journal of Neuroscience.(Click here for details. [in Japanese])
2013-10-31: “Press Release”
The research group led by the Principal Investigator of the Foundation of Synapse and Neurocircuit Pathology project, Hitoshi Okazawa (Professor, Medical Research Institute, Tokyo Medical and Dental University) identified novel molecules that contribute to the pathology of spinocerebellar ataxia type1 (SCA1). Okazawa's group combined Drosophila genetics screening and systems biology analysis to identify disease-modifying genes. They finally identified RpA1, a critical regulator of DNA damage repair through homologous recombination and some other types of DNA damage repair, and Chk1, a critical transducer of DNA damage response signaling, as major contributors to the SCA1 pathology. They also succeeded in remarkable elongation of lifespan in the SCA1 fly model. These results have been published online in Human Molecular Genetics.(Click here for details.)
2013-10-31: “Press Release”
Ca²⁺-dependent activator protein for secretion 1 (CAPS1) plays a regulatory role in the dense-core vesicle (DCV) exocytosis pathway, but its functions in the brain are largely unknown because of neonatal death soon after birth in Caps1 knockout mice. To clarify the functions of the protein in the brain, Dr. Sadakata and his colleagues generated conditional knockout (cKO) mouse lines, lacking Caps1 in the brain. Brain-specific Caps1 cKO mice had decreased immunoreactivity for brain-derived neurotrophic factor (BDNF) along the cerebellar climbing fibers. At climbing fiber-Purkinje cell synapses, the number of DCVs was markedly lower and the number of synaptic vesicles was also reduced. Correspondingly, the mean amplitude of excitatory postsynaptic currents was decreased, whereas paired-pulse depression was significantly increased. Their results suggest that the association of diabetes and depression. (Click here for details. [in Japanese])
2013-10-11: “Press Release”
A study group led by Guest Researcher Makoto Kinoshita (professor at Nagoya University Graduate School of Science) has found a novel molecular mechanism that optimizes the balance between the stability and dynamicity of microtubules for perinatal neuritogenesis. The group showed that septin filaments are required as physical scaffolds for the coordination of HDAC6-mediated deacetylation/destabilization of microtubules in developing mouse brain. The novel tripartite molecular interaction will help understand the synapse circuit pathology, as HDAC6 inhibitors have been tested for therapeutic applications for neurodegenerative disorders and the quantitative/qualitative dysregulations of septins are implicated in Parkinson's disease and hereditary neuropathy. (Click here for details. )
2013-09-24: “Press Release”
Guest Researcher Shin Kwak (professor at International University of Health and Welfare) and Project Researcher Takenari Yamashita at the University of Tokyo's Graduate School of Medicine, Center for Disease Biology and Integrative Medicine, in collaboration with a Jichi Medical University group, have succeeded in gene therapy for sporadic amyotrophic lateral sclerosis (ALS) using an intravenous injection of AAV9 vector-mediated delivery of the gene for human adenosine deaminase acting on RNA 2 (ADAR2) using AR2 mice. The research group has developed adeno-associated virus serotype 9 (AAV9) vectors that enable gene delivery to the neurons via intravenous injection. A single injection of AAV9-ADAR2 vectors in the tail vein, even after the initiation of motor dysfunction, rescued progressive motor dysfunction and prevented motor neurons from death with normalizing TDP-43 expression in the AR2 mice. This AAV9-mediated ADAR2 gene delivery may therefore be a realistic gene therapy for sporadic ALS when safety concerns and optimal dosages are resolved. (Click here for details. [in Japanese])
2013-09-01: The summer workshops of the Comprehensive Brain Science Network were held at the Nagoya Congress Center, between August 29 and September 1, 2013.
The summer meeting of the Synapse Pathology research group was held as part of these workshops. (click here to see program [in Japanese]). (Click here for the photo gallery from the meeting).
2013-07: News Letter Vol. 2 has been released.
2013-07-11: An advanced training course on two-photon microscopy was held at RIKEN on July 11 2013.
2013-07-10: A basic training course on two-photon microscopy was held at Tokyo Medical and Dental University on July 10 2013. (Click here for the photo gallery from the course)
2013-05-08: “Press Release”
The research group led by the Principal Investigator of the Foundation of Synapse and Neurocircuit Pathology project, Hitoshi Okazawa (Professor, Medical Research Institute, Tokyo Medical and Dental University) identified a common pathological signal mediated by TERA/VCP/p97 that links multiple groups of neurodegenerative diseases. Impaired function of this molecule has been suggested in frontotemporal lobar degeneration. Okazawa's group has shown that impaired function of TERA/VCP/p97 is also involved in more than one polyglutamine disease. The pathway is the following: abnormal proteins bind to TERA/VCP/p97 impairing its function, specifically, the function to repair DNA damage, which leads to degeneration. These results have been published online in Nature Communications.(Click here for details. [in Japanese])
2013-04-01: Priority topics for research in which public funds are available have now been released. For further details, please access the Organization/Members page, and one of the following dedicated pages: Synapse Pathology, Circuit Pathology, or New Techniques.
2013-03-18: “Press Release”
In a joint effort with other investigators, two members of the Publicly Invited Research group, Nobuhisa Iwata (Professor, School of Pharmaceutical Sciences, Nagasaki University) and Shinichi Muramatsu (Professor, Department of Neurology, Jichi Medical University), developed a virus vector that can be administered into blood vessels and causes gene expression only in neurons in the brain. Using a mouse model of Alzheimer's disease, the authors also demonstrated that the administration of this virus improves cognitive functioning of impaired mice to equivalent levels in wild mice. If safety concerns are resolved and mass production technology is developed, this virus vector can be used clinically for the treatment of Alzheimer's disease. These results have been published in Scientific Reports.(Click here for details. [in Japanese])
2013-02-22: “Press Release”
This press release, issued by Kyoto University, outlines the results of collaborative research conducted by a Planned Research team member, Haruhisa Inoue (Associate Professor, Center for iPS Cell Research and Application, Kyoto University) and a Publicly Invited Research team member, Nobuhisa Iwata (Professor, Nagasaki University School of Pharmaceutical Sciences). Using patient-derived induced pluripotent stem cells, the authors elucidated a pathological mechanism of Alzheimer's disease, and the results were published in the journal Cell Stem Cell. (Click here for details. [in Japanese])
2012-12-19: “Press Release”
Shin Kwak (Associate Professor, International University of Health and Welfare; Visiting Researcher, Clinical Biotechnology Laboratory, Center for Disease Biology and Integrative Medicine, The University of Tokyo) and colleagues were the first to elucidate a cell death cascade in which abnormal expression of calcium-permeable AMPA receptors, induced by defects in RNA editing of AMPA receptor subunits, causes TDP-43 pathology through the activation of calpain, a proteinase. (Click here for details. [in Japanese])
2012-12-15: The winter meeting of the Synapse Pathology research group was held at KKR Kamakura Wakamiya on December 15 and 16, 2012. (Click here for the photo gallery from the event.)
2012-11-05: Organized by Dr. Hayashi (Planned Research team member) and colleagues, the Cold Spring Harbor Asia meeting "Neural Circuit Basis of Behavior and its Disorders" was held in Suzhou, China. Approximately 100 researchers attended the meeting.
2012-10-18: “Press Release”
The research group led by Dr. Takeshi Iwatsubo revealed the activity-dependent proteolytic processing of neuroligin proteins, which are implicated in synaptogenesis and autism spectrum disorders. This proteolysis decreases the cell surface levels of neuroligin proteins and regulates the synaptogenic activity. They also identified that ADAM10 and γ-secretase are responsible enzymes for this pathway. This result indicates that neuronal activity-dependent synaptic function is regulated by proteolysis of synaptic membrane proteins. These results have been published in Neuron. (Click here for details. [in Japanese])
2012-09-01: There is a call for applications to the Publicly Invited Research projects for FY2013–14. Application guidelines can be downloaded from the Continued Research Area at http://www.mext.go.jp/a_menu/shinkou/hojyo/boshu/1324980.htm (a website of the Ministry of Education, Culture, Sports, Science and Technology of Japan [in Japanese]). A research outline (contents of recruited Publicly Invited Research projects) can be directly downloaded from here (click to download [in Japanese]).
2012-08-02: “Press Release”
This press release, issued by Kyoto University, outlines the findings of a Planned Research project led by Planned Research team member, Haruhisa Inoue (Associate Professor, Center for iPS Cell Research, Kyoto University). Dr. Inoue has been working on the use of disease-specific iPS cells to conduct a pathological analysis of ALS, and his paper has been published in Sci Transl Med. Dr. Inoue’s outstanding work means that development can now begin on the discovery of therapeutic drugs for ALS. (Click here for details.)
2012-07-25: The “Joint Symposium for Three Scientific Research on Innovative Areas on Brain Disease” was held at Sendai International Center on July 25 2012. (Program) (Click here for the photo gallery from the event.)
2012-07-24: The summer meeting of the Synapse Pathology research group was held at Sendai International Center on July 24 2012. (Program) (Click here for the photo gallery from the event.)
2012-03-23: “Press Release”
This press release, issued by Kyoto University, outlines the findings of a Planned Research project led by Publicly Invited Research team member, Tomoo Hirano (Professor, Graduate School of Science, Kyoto University). Dr. Hirano has been working on the development of new experimental techniques to visualize the movement of APMA receptors inside and outside the postsynaptic membrane. His research has made it possible to observe changes in AMPA receptors during long-term potentiation. (Click here for details.)
2012-03-14: “Press Release”
This press release, issued by Yokohama City University, outlines the findings of a Planned Research project led by Publicly Invited Research team member, Naomichi Matsumoto (Professor, Yokohama City University Graduate School of Medicine). Dr. Matsumoto discovered that mutations in chromatin remodeling complex can cause Coffin-Siris syndrome, a disorder causing developmental delays, and his paper outlining this work was published in Nature Genetics. The identification of the responsible gene raises hopes that the pathology of Coffin-Siris syndrome can be better understood, leading to the development of therapies and improvements in clinical conditions. (Click here for details. [in Japanese])
2012-02-22: Planned Research team member, Takeshi Iwatsubo (Professor, Neuropathology, Faculty of Medicine, Graduate School of Medicine, The University of Tokyo) has been awarded the 2012 Potamkin Prize by the American Academy of Neurology. This globally recognized prize is awarded to persons who have made major contributions to the understanding of Alzheimer’s through research. (Click here for details. [in Japanese])
2012-02-10: The International Symposium "Fragile X, Autism and Intellectual Disabilities" was held. (Location: M&D Tower Akio Suzuki Memorial Hall, Tokyo Medical and Dental University)　(Program) (Click here for the photo gallery from the event.)
2012-01-18: “Press Release”
Tokyo Medical and Dental University issued a press release detailing the results of Professor Takanori Yokota’s Publicly Invited Research. He and his team developed a primate model of amyotrophic lateral sclerosis (ALS), which is expected to significantly contribute to the understanding of the mechanisms underlying ALS. (Click here for details. [in Japanese])
2011-12-17,18: The Foundation of Synapse and Neurocircuit Pathology held its Winter Meeting. (Location: KKR Hotel Atami, Atami) (Click here for the photo gallery from the event.)
2011-11-11: Professor Naomichi Matsumoto of Yokohama City University, a member of Publicly Invited Research group, received an award from the Japan Society of Human Genetics at its 56th Annual Meeting for his work on “A series of studies in genomic medicine including those on the discovery of disease genes of various single gene disorders and clarification of their molecular pathogenesis.” (Click here for details. [in Japanese])
2011-11-01: “Press Release”
Professor Masahiko Takada of the Primate Research Institute at Kyoto University, a member of Publicly Invited Research group, discovered that movement disorders in Parkinson’s disease are caused by oscillatory phenomena in the basal ganglia, and temporary inhibition of such phenomena can halt the movements. (Click here for details. [in Japanese])
2011-10-21: “Press Release”
RIKEN issued a press release detailing the results of a study by Nobuyuki Nukina’s team. He showed that degradation of the gene product involved in Huntington's disease is regulated by phosphorylation of p62. These results are expected to lead to the clarification of the mechanism by which site specificity of neurodegeneration is determined (circuit pathology). (Click here for details. [in Japanese])
2011-09-22: “Press Release”
Tokyo University issued a press release detailing the results of a study by Lecturer Tomoyuki Yoshida, a member of Publicly Invited Research group. He discovered that IL1RAPL1 protein, which is involved in intellectual disabilities and autism, is responsible for the creation of the cranial nerve network by binding to PTPδ to form a synaptic organizing complex. These results are expected to help clarify the pathogenesis of neurodevelopmental disorders. (Click here for details. [in Japanese])
2011-09-21: Toshihide Yamashita, member of Publicly Invited Research, has been named the winner of the 29th Osaka Science Prize. Click here to view the article (only available in Japanese)
2011-08-21: The Summer Workshop of the Comprehensive Brain Science Network held on 2011.8.21–8.24 (Location: Kobe International Conference Center, Kobe).
Summer Meeting of Foundation of Synapse and Neurocircuit Pathology (Click here for a photo gallery of the event) held on 2011.8.21–8.22, and Symposium of Young Scientists (Click here for a photo gallery of the event) held on 2011.8.23 in this workshop.
2011-07: News Letter volume 1 has been published.
2011-07-13: Technical training course of iPS cells held on July 13th (Location: CiRA Kyoto University).
2011-06-08: Advanced training course of two-photon microscope held on June 8th (Location: RIKEN Brain Science Institute).
2011-05-18: Hitoshi Okazawa, Professor at Tokyo Medical and Dental University and Principal Investigator of the Foundation of Synapse and Neurocircuit Pathology Scientific Research in Innovative Areas project, has received the Narabayashi Prize 2011 at the 52nd Annual Meeting of the Japanese Society of Neurology.
2011-05-17: Basic training course of two-photon microscope held on May 17th, 24th, 27th and June 1st (Location: M&D Tower, Tokyo Medical and Dental University).
Click here for a photo gallery of the event
2011-04-01: New Research Projects were selected from open competition. Details will be up on HP soon.
2011-03-21: “Press Release”
Osaka University issued a press release detailing the results of a study by Professor Toshihide Yamashita, a member of Publicly Invited Research group. He discovered that repulsive guidance molecule (RGM) proteins promote the activation of T cells and clarified the underlying molecular mechanisms. These results were published in Nature Medicine and are expected to lead to the development of new molecular target therapies for multiple sclerosis. (Click here for details. [in Japanese])
2011-01-17: Two-photon microscope set up complete. Device reservation system now active on site (currently available in Japanese only).
2011-01-17: *Outreach Activity*
Yasunori Hayashi, Team Leader at the Brain Science Institute, RIKEN, gave a lecture to students from National Tax College as a part of their social awareness activity.
2010-11-30: *Steering Committee News*
International Evaluation Committee members Professor Erich Wanker and Professor Craig Powell give positive feedback on Kick-off International Symposium and Innovative Areas project. Click here to see Professor Erich Wanker's comments and here to see Professor Craig Powell's comments.
2010-10-27: First meeting of Steering Committee held, meeting joined by an auditor from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).
2010-10-27: Kick-off International Symposium. 2010.10.27 (Location: M&D Tower Big Hall, Tokyo Medical and Dental University)
Click here for a photo gallery of the event
2010-10-20: *Press Release*
Japan Science and Technology Agency and Tokyo Medical and Dental University issued a press release detailing the achievements of Hitoshi Okazawa, Professor at Tokyo Medical and Dental University and Principal Investigator of the Foundation of Synapse and Neurocircuit Pathology Scientific Research in Innovative Areas project. The release is particularly focused on Dr. Okazawa's achievements in linking a decline in the functionality of PQBP1, which binds to proteins causative of Huntington's disease, and induces dysfunction of synaptic plasticity. Dr. Okazawa's research has achieved significant attention because of its potential for elucidating the mechanisms of dementia caused by degenerative disease.
Click here to view the press release (only available in Japanese)
2010-10-14: *Outreach Activity*
Noboyuki Nukina, Planning Committee member and Team Leader of Structural Neuropathology, Brain Science Institute, RIKEN, participated in the 40th Health & Science Twenty-Twenty Pfizer Press Conference, delivering a lecture on gene therapy research currently being carried out into Huntington's disease.
2010-10-08: *Outreach Activity*
Hitoshi Okazawa, Professor at Tokyo Medical and Dental University and Principal Investigator of the Foundation of Synapse and Neurocircuit Pathology Scientific Research in Innovative Areas project, gave a lecture to academics and the general public as part of a program of lectures arranged by four leading universities for the benefit of the academic and local communities. This is the fifth time the program has been run. Dr. Okazawa's lecture was subsequently covered by the Nihon Keizai Shimbun newspaper on November 1.
Click here to view the article (only available in Japanese)
2010-09-23: *Paper Published*
Masahisa Katsuno, Planning Committee member and Associate Professor of Neuropathology at the Institute for Advanced Research, Nagoya University, has had a paper detailing his latest finding included in the latest edition of PLoS One, a peer-reviewed journal. The paper clarifies the comprehensive molecular changes in skeletal muscle, which is controlled by motor neuron synapses. These changes help to advance the neurodegenerative molecular pathogenesis seen in motor neuron diseases mediated by TGF-β signaling.
Click here for further details (only available in Japanese)
2010-08-20: *Outreach Activity*
Yasunori Hayashi, Team Leader at the Brain Science Institute, RIKEN, showed high school students around his laboratory as part of a High School Student Summer School in Physiology organized in recognition of International Brain Week.
2010-07-27: The summer workshop of the Comprehensive Brain Science Network. 2010.7.27–7.30 (Location: Hotel Sapporo Geibunkan, Sapporo)
Click here to see a photo gallery

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