News & Topics

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] )

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