Research

Identification of novel molecular mechanisms that modulate neurodegeneration

Profile

Takeshi Fujiwara

Takeshi Fujiwara (Specially Appointed Associate Professor)

 

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Working address

Division of Biochemistry

Department of Biochemistry and Molecular Biology

Osaka University Graduate School of Medicine

Yamada-oka 1-3, Suita 565-0871, Osaka, Japan

Tel: +81-6-6879-4606

Fax: +81-6-6879-4609

E-mail: fujiwara@anat3.med.osaka-u.ac.jp

 

Education

1993 March    B.S.,    Osaka University School of Science

1995 March    M.S.,    Osaka University School of Science

1999 March    Ph.D.,  Osaka University Graduate School of Medicine

 

Professional history

1996 April - 1999 March             Research Fellow of the Japan Society for the

                                                       Promotion of Science

1999 April - 1999 September    ERATO Takai Biotimer Project, Research

                                                       Fellow

1999 October - 2002 April          Vanderbilt University School of Medicine (Dr.

                                                       Brigid Hogan), Postdoctoral Fellow

2002 May - 2005 March              Dana-Farber Cancer Institute, Harvard

                                                       Medical School (Dr. David Pellman),

                                                       Postdoctoral Fellow

2005 April - 2008 December     KAN Research Institute, Principal Investigator

2009 January - Present              Osaka University Graduate School of

                                                       Medicine, Specially Appointed Associate

                                                       Professor

 

Academic Membership

American Society for Cell Biology: Member

The Japan Neuroscience Society: Member

Summary

Our research focuses on identifying novel molecular mechanisms that could modulate/protect axons and cell bodies of neurons from degeneration. We use primary hippocampal cultured neurons from rat and mice and glutamate excitotoxicity as a model system to degenerate neurons so that we can identify molecules/proteins responsible for modulating/protecting axons and cell bodies from glutamate excitotoxicity. We also use various techniques including molecular cell biological and biochemical techniques as well as immunohistohemical techniques on brain tissues of patients with Alzheimer's disease, obtained in collaboration with the Brain Research Institute, University of Niigata.  

We identified dynein and dynactin components, p150Glued and dynein intermediate chain (DIC), as novel regulators that could modulate the degeneration of neurons caused by glutamate excitotoxicity.  As glutamate excitotoxicity is implicated in chronic neurological disorders, including Alzheimer's disease and amyotrophic lateral sclerosis, and acute central nervous system insults such as ischemia, the molecular mechanism that we identified might modulate neurodegeneration seen in various neurological disorders. We found that p150Glued, a major component of the dynactin complex, was truncated at the C-terminal region induced by glutamate excitotoxicity. When overexpressed in neurons, the p150Glued C-terminal truncated form exacerbated axon degeneration and cell body death induced by glutamate excitotoxicity. Importantly, the p150Glued C-terminal truncated form was identified in brain tissues from the frontal cotex in patients with Alzheimer's disease, implicating relevance of our in vitro findings on the mechanism underlying the onset and progression of Alzheimer's disease. We futher found that overexpression of wild-type DIC, a major component of the dynein complex, as well as wild-type p150Glued protect axons and cell bodies from glutamate excitotoxicity-induced degeneration (see schema).

We are currently extending our research to decipher how p150Glued and DIC exert modulating functions on the process of axon degeneration. We are using compartmentalized axons using a microfluidic device (AXIS, Millipore), and biochemical strategies to answer our questions. We are also investigating whether localization of p150Glued, DIC, and relevant proteins are altered in human brains with neurological disorders, e.g. Alzheimer's disease.

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Selected publication

 1.   Fujiwara T.* and Morimoto K.

    Inhibition of p53 transactivation functionally interacts with microtubule stabilization to

    suppress excitotoxicity-induced axon degeneration.

    Biochemical and Biophysical Research Communications, in press, 2012.  

   * : correspondence

 

2.  Fujiwara T.* and Morimoto K.

    Cooperative effect of p150Glued and microtubule stabilization to suppress

    excitotoxicity-induced axon degeneration.

    Biochemical and Biophysical Research Communications, 424 (1), 82-88, 2012.

     * : correspondence  

 

3. Fujiwara T.*, Morimoto K., Kakita A., and Takahashi H. 

    Dynein and dynactin components modulate neurodegeneration induced by

    excitotoxicity.  

    Journal of Neurochemistry,  122 (1), 162-174,  2012.   * : correspondence 

Some of Recent Papers

Publications (original paper: peer reviewed) 

 

1.        Fujiwara T.* and Morimoto K.

Inhibition of p53 transactivation functionally interacts with microtubule stabilization to suppress excitotoxicity-induced axon degeneration.

       Biochem. Biophys. Res. Commun., in press, 2012.   * : correspondence

 

2.        Fujiwara T.* and Morimoto K.

Cooperative effect of p150Glued and microtubule stabilization to suppress excitotoxicity-induced axon degeneration.

Biochem. Biophys. Res. Commun., 424 (1), 82-88, 2012.   * : correspondence

 

3.       Fujiwara T.*, Morimoto K., Kakita A., and Takahashi H.

Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity.

J. Neurochem., 122 (1), 162-174, 2012.   * : correspondence

 

4.       Tanaka, K., Yokoi, S., Morimoto, K., Iwata, T., Nakamoto, Y., Nakayama, K., Koyama, K., Fujiwara, T., and Fukase, K.

Cell surface biotinylation by azaelectrocyclization: easy-handling and versatile approach for living cell labeling.

Bioorg. Med. Chem., 20 (6), 1865-1868, 2012.

 

5.        Fujiwara, T.*, Kawakatsu, T., Tayama, S., Kobayashi, Y., Sugiura, N., Kimata, K., and Takai, Y.

Hyaluronan-CD44 pathway regulates orientation of mitotic spindle in normal epithelial cells.

Genes Cells, 13 (7), 759-770, 2008.   * : correspondence

 

6.        Fujiwara, T., Bandi, M., Ivanova, E. V., Nitta, M., Bronson, R., and Pellman, D.

Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells.

Nature, 437 (7061), 1043-1047, 2005.

 

7.        Fujiwara, T., Dehart, D. B., Sulik, K. K., and Hogan, B. L. M.

Distinct requirements for extraembryonic and embryonic Bone Morphogenetic Protein 4 in the formation of the node and primitive streak, and coordination of left-right asymmetry in the mouse.

Development, 129 (20), 4685-4696, 2002.

 

8.        Fujiwara, T., Dunn, N. R., and Hogan, B. L. M.

Bone Morphogenetic Protein 4 in the extraembryonic mesoderm is required for allantois development and the localization and survival of primordial germ cells in the mouse.

Proc. Natl. Acad. Sci. USA, 98 (24), 13739-13744, 2001.

 

9.       Ozaki-Kuroda, K., Yamamoto, Y., Nohara, S., Kinoshita, M., Fujiwara, T., Irie, K., and Takai, Y.

Dynamic localization and function of Bni1p at the sites of directed growth in yeast Saccharomyces cerevisiae.

Mol. Cell. Biol., 21 (3), 827-839, 2001.

 

10.    Fujiwara, T., Mammoto, A., Kim, Y., and Takai, Y.

Rho small G-protein-dependent binding of mDia to an Src homology 3 domain-containing IRSp53/BAIAP2.

Biochem. Biophys. Res. Commun., 271 (3), 626-629, 2000.

 

11.    Fujiwara, T., Tanaka, K., Inoue, E., Kikyo, M., and Takai, Y.

Bni1p regulates microtubule-dependent nuclear migration through the actin cytoskeleton in Saccharomyces cerevisiae.

Mol. Cell. Biol., 19 (12), 8016-8027, 1999.

 

12.    Kikyo, M., Tanaka, K., Kamei, T., Ozaki, K., Fujiwara, T., Inoue, E., Takita, Y., Ohya, Y., and Takai, Y.

An FH domain-containing Bnr1p is multifunctional protein interacting with a variety of cytoskeletal proteins in Saccharomyces cerevisiae.

Oncogene, 18 (50), 7046-7054, 1999.

 

13.    Mino, A., Tanaka, K., Kamei, T., Umikawa, M., Fujiwara, T., and Takai, Y.

Shs1p: A novel member of Septin that interacts with Spa2p, involved in polarized growth in Saccharomyces cerevisiae.

Biochem. Biophys. Res. Commun. 251 (3), 732-736, 1998.

 

14.    Fujiwara, T., Tanaka, K., Mino, A., Kikyo, M., Takahashi, K., Shimizu, K., and Takai, Y.

Rho1p-Bni1p-Spa2p interactions: Implication in localization of Bni1p at the bud site and regulation of the actin cytoskeleton in Saccharomyces cerevisiae.

Mol. Biol. Cell, 9 (5), 1221-1233, 1998.

 

15.    Kumagai, H., Fujiwara, T., Matsubara, H., and Saeki, K.

Membrane localization, topology, and mutual stabilization of the rnfABC gene products in Rhodobacter capsulatus and implications for a new family of energy-coupling NADH Oxidoreductases.

Biochemistry, 36 (18), 5509-5521, 1997.

 

16.    Kohno, H., Tanaka,K., Mino, A., Umikawa, M., Imamura, H., Fujiwara, T., Fujita, Y., Hotta, K., Qadota, H., Watanabe, T., Ohya, Y., and Takai, Y.

Bni1p implicated in cytoskeletal control is a putative target of Rho1p small GTP-binding protein in Saccharomyces cerevisiae.

EMBO J., 15 (22), 6060-6068, 1996.

 

17.    Nonaka, H., Tanaka, K., Hirano, H., Fujiwara, T., Kohno, H., Umikawa, M., Mino, A., and Takai, Y.

A downstream target of RHO1 small GTP-binding protein is PKC1, a homolog of protein kinase C, which leads to activation of the MAP kinase cascade in Saccharomyces cerevisiae.

EMBO J., 14 (23), 5931-5938, 1995.

 

18.    Saeki, K., Tokuda, K., Fujiwara, T., and Matsubara, H.

Nucleotide sequence and genetic analysis of the region essential for functional expression of the gene for Ferredoxin I, fdxN, in Rhodobacter capsulatus: sharing of one upstream activator sequence in opposite directions by two operons related to nitrogen fixation.

Plant Cell Physiol., 34 (2), 185-199, 1993.  

 

 

News (topics)

 

1.        Pellman, D. and Fujiwara (Scopus) 

Extra Centrosomes and Chromosomes Promote Tumors in Mice and May Be a Target for Therapy - Double trouble: Cells with duplicate genomes can trigger tumors.

Cancer Biol. Ther., 4 (11), 1173, 2005. 

 

2.        ScienceDaily, Science NewsOctober 13, 2005

Double Trouble: Cells With Duplicated Genomes Can Trigger Tumors.

 

3.        The Science Advisory Board, Biomedical NewsOctober 13, 2005

Cells With Duplicated Genomes Can Trigger Tumors.

 

 

International Meetings 

 

1.        The 50th Annual Meeting of the American Society for Cell Biology (December, 2010, in Philadelphia)

Microtubule stabilization and retrograde transport proteins prevent axon degeneration.

Takeshi Fujiwara, Koji Morimoto, Toshihide Yamashita, and Yoshihiro Yoneda

 

2.        8th International Conference (Hyaluronan 2010): international society for hyaluronan sciences (June, 2010, in Kyoto)

Hyaluronan-CD44 pathway regulates orientation of mitotic spindle in normal epithelial cells.

Takeshi Fujiwara, Tomomi Kawakatsu, Sayaka Tayama, Yasuyo Kobayashi, Nobuo Sugiura, Koji Kimata, and Yoshimi Takai.

 

3.        International Symposium on Organelle Network: Interface among Infection-Immunity, Cell Biology and Glycobiology (April, 2010, in Osaka)

Role of microtubules and retrograde transport protein on axon degeneration.

Takeshi Fujiwara, Koji Morimoto, Toshihide Yamashita, and Yoshihiro Yoneda

 

4.        The 43rd Annual Meeting of the American Society for Cell Biology (December, 2003, in San Francisco)

Ploidy-specific lethality in mouse embryonic stem cells.

Takeshi Fujiwara, Madhavi Bandi, and David Pellman

 

5.        The 4th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association "Innovative Approaches to the Prevention, Diagnosis, and Therapy of Cancer" (February, 1998, in Maui, USA).

Dynamic activation and action of the Rho family of small G proteins in regulation of the actin cytoskeleton.

Takeshi Fujiwara, Kazuma Tanaka, Masato Umikawa, Takuya Sasaki, and Yoshimi Takai