Kazuhiko Namikawa

Kazuhiko Namikawa

K. Namikawa

  • E-Mail: k.namikawa[at]tu-braunschweig.de

  • Telefon: +49 (0) 531 391 3234

  • Telefax: +49 (0) 531 391 8178

  • Anschrift:

    TU Braunschweig
    Biozentrum
    Zoologisches Institut
    Zelluläre und Molekulare Neurobiologie
    Spielmannstr. 7
    38106 Braunschweig

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Neurological Disease Modeling in Zebrafish

Research interest : Neurological Disease Modeling in Zebrafish    

The evidence that approximately 80 % of human disease related genes are conserved in the zebrafish genome provides us with the chance to generate genetically inherited disease models not only for understanding the disease etiology, but also for evaluating potent compounds against human diseases.

Since zebrafish larvae are maintained in an aqueous environment in multi-well plates where chemicals can be easily applied, it is possible to study and validate drug effectiveness in terms of therapeutic concentrations, side effects and feasibility to cross the blood brain barrier.

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Fig.2 Zebrafish Kcnc3a subunit reveals the S1-S6 transmembrane segments homologous to those in mammals. The third positively charged arginine residue in the S4 segment is substituted by histidine (R335H), which mimics SCA13R420H in human patients.

By making use of the established disease zebrafish, we are currently investigating: (1) cell biology of disease affected neurons, and (2) neuron-glia communication during progression of neurodegeneration in vivo. 

Furthermore, our model will enable us to (3) validate the effectiveness of potent compounds towards mitigating these untreatable neurodegenerative diseases.

Please feel free to contact me if you get interested in our disease zebrafish models, or tools we developed.

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Fig.1 Transgenic zebrafish expressing GFP and TagRFP-T in cerebellar Purkinje neurons.

To take these advantages of zebrafish, we have been working on a project aiming to develop zebrafish disease models for Spinocerebellar Ataxia (SCA), a class of neurodegenerative diseases, in which patients display progressive cerebellar atrophy and suffer from loss of motor coordination.

We already developed a cerebellar Purkinje neuron specific multi-color labeling method using a bidirectional expression system in transparent zebrafish (Fig. 1) in order to monitor pathophysiological processes occurring in degenerating neurons.

We have established transgenic zebrafish model mimicking SCA type 13 by overexpressing its causative mutant of KCNC3, a voltage gated potassium channel (Fig.  2, 3, and Movie).

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Fig. 3 (Upper) A PC-specific transgene construct to express Kcnc3awt, or Kcnc3aR335H together with nuclear localized H2B-EGFP and membrane targeted Fyn-TagRFP-T reporter genes linked to a self-cleaving T2A-peptide. (Lower) Zebrafish PCs expressing Kcnc3aR335H show degenerative changes with fragmented red labelled puncta from dendritic or axonal structures. cpce: Purkinje neuron specific enhancer element.

Open positions

Positions for students to write bachelor/master thesis, or the internship course to acquire basic skills of molecular biology, culturing mammalian cells, or in vivo zebrafish imaging (at least for 3 months, or longer) are available. I would be also happy to assist you to write a grant proposal to support your stay in our group for PhD study/or Post-doc research.

Review articles describing our zebrafish models

  1. Cvetanovic M (2019), Non-invasive imaging of neurodegeneration in live animals, SCAsource (Link)
  2. Esch T (2019). This week in The Journal: Purkinje-Cell-Specific Expression of Mutant Kv3.3 in Zebrafish. J Neurosci. 39(20):3783 (Link).
  3. Namikawa, K*., Dorigo, A., Köster, RW*. (2019) Neurological Disease Modelling for Spinocerebellar Ataxia Using Zebrafish. (Article Commentary) J Exp Neurosci. 13:1-5.  (*corresponding author) (Link)
Journal cover

Original articles related to the current research

  1. Namikawa K*., Dorigo, A., Zagrebelsky, M., Russo, G., Kirmann, T., Fahr, W., Dübel, S., Korte, M., Köster, R. W*.  (2019) Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System. J Neurosci. 39(20):3948-3969. (*corresponding author) (Pubmed)          
  2. Weber, T.*, Namikawa, K*. (* equally contributed), Winter, B., Müller-Brown, K., Kühn, R., Wurst, W., & Köster, R. W. (2016)  Caspase-mediated apoptosis induction in zebrafish cerebellar Purkinje neurons. Development. 143: 4279-4287.  (Pubmed)
  3. Matsui, H., Namikawa, K., Babaryka, A. & Köster, R. W. (2014) Functional regionalization of the teleost cerebellum analyzed in vivo. Proc. Natl. Acad. Sci. U. S. A. 111 (32), 11846–51. (Pubmed) (Highlight in PNAS)

VITA

Work experience:

Since 2013: Research fellow (permanent faculty position), Zoological Institute, Division of Cellular and Molecular Neurobiology, Technical University of Braunschweig, Germany

  • Neurological disease modeling using zebrafish
     

2011-2013: Research fellow, Zoological Institute, Department of Cell biology and Cell Physiology, Technical University of Braunschweig, Germany

  • Neurological disease modeling using zebrafish
     

2006-2010: Research fellow, Institute of Developmental Genetics, Zebrafish Neuroimaging Group, Helmholtz Center, Munich-Neuherberg, Germany

  • Neurological disease modeling using zebrafish
     

2005-2008: Associate professor, Department of Anatomy and Neuroscience, Asahikawa Medical University, Japan

  • Biological roles of macrophages during nerve regeneration (published in J Neurosci (Pubmed) )
     

2001-2005: Assistant professor, Department of Anatomy and Neurobiology, Osaka City University, Graduate School of Medicine Japan

  • Biological roles of macrophages during nerve regeneration
  • Establishment of tissue specific adenoviral gene transduction system
     

1999-2001: Assistant professor, Department of Anatomy, Asahikawa Medical College, Japan

  • Cell biology of regenerating motor neurons

 

Education:

1995-1999: Ph.D. Study (Ph.D. degree in medicine, 2000, Osaka University, Japan)

  • Doctoral thesis “ Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration” (published in J Neurosci (Pubmed), Supervised by Professor Dr. Hiroshi Kiyama (Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine)

1993-1995: Master Study (Master degree in Medical science, Osaka University, Japan)

1992-1993: Research student, Department of Developmental Medical Sciences, Division of Health Science, Faculty of Medicine, University of Tokyo, Japan

1990-1992: Undergraduate Study in Health Science, Division of Health Science, Faculty of Medicine, University of Tokyo, Japan

1998-1990: Undergraduate Study in Natural Sciences, University of Tokyo, Japan

 

Teaching:

Current teaching activities at Technical University of Braunschweig:

  • Lecture
    ZB28 Genetics and cell biology of neurological diseases
  • Seminar
    ZB23 Cell biology of human diseases
  • Practical course
    ZB21 Neuronal Cell biology (2 weeks)
    Mz01 Neuronal Cell biology (2 weeks)
    ZB23/Mz06 (4 weeks/6 weeks advanced lab course)

Past teaching experiences:

  • Developmental biology (Lectures and practical course)
  • Human anatomy (lectures and practical course)
  • Neuroanatomy  (lectures and practical course)
  • Histology (lectures and practical course)

Publication list 

  1. Li J., Ünal C., Namikawa, K., Michael Steinert M., & Köster, RW. (2020) Development of a Larval Zebrafish Infection Model for Clostridioides difficile. J Vis Exp. (156). doi: 10.3791/60793.
  2. Namikawa, K*., Dorigo, A., & Köster, RW*. (2019) Neurological Disease Modelling for Spinocerebellar Ataxia Using Zebrafish. (Article Commentary) J Exp Neurosci. 13:1-5.  (* corresponding author)
  3. Namikawa, K*., Dorigo, A., Zagrebelsky, M., Russo, G., Kirmann, T., Fahr, W., Dübel, S., Korte, M., & Köster, RW*. (2019) Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System. J Neurosci. 39(20):3948-3969. (* corresponding author)
  4. Matsui, H., Kenmochi, N., & Namikawa, K. Age- and α-Synuclein-Dependent Degeneration of Dopamine and Noradrenaline Neurons in the Annual Killifish Nothobranchius furzeri. (2019) Cell Rep. 26(7):1727-1733.e6.
  5. Weber, T.*, Namikawa, K*. (* equally contributed), Winter, B., Müller-Brown, K., Kühn, R., Wurst, W., & Köster, R. W. (2016)  Caspase-mediated apoptosis induction in zebrafish cerebellar Purkinje neurons. Development. 143: 4279-4287
  6. Matsui, H., Namikawa, K., & Köster, R. W. (2014) Identification of the zebrafish red nucleus using Wheat Germ Agglutinin transneuronal tracing. Commun. Integr. Biol. 7 (6), e994383.
  7. Matsui, H., Namikawa, K., Babaryka, A. & Köster, R. W. (2014) Functional regionalization of the teleost cerebellum analyzed in vivo. Proc. Natl. Acad. Sci. U. S. A. 111 (32), 11846–51.
  8. Konishi, H., Matsumoto, S., Namikawa, K. & Kiyama, H. (2013) N-terminal cleaved pancreatitis-associated protein-III (PAP-III) serves as a scaffold for neurites and promotes neurite outgrowth. J. Biol. Chem. 288, 10205–13.
  9. Oehninger, L., Stefanopoulou, M., Alborzinia, H., Schur, J., Ludewig, S., Namikawa, K., Munoz-Castro, A., Köster, R. W., Baumann, K., Wolfl, S., Sheldrick, W. S. & Ott, I. (2013) Evaluation of arene ruthenium(II) N-heterocyclic carbene complexes as organometallics interacting with thiol and selenol containing biomolecules. Dalt. Trans. 42 (5), 1657–66.
  10. Sasmal, P. K., Carregal-Romero, S., Han, A. A., Streu, C. N., Lin, Z., Namikawa, K., Elliott, S. L., Köster, R. W., Parak, W. J. & Meggers, E. (2012). Catalytic azide reduction in biological environments. Chembiochem 13 (8), 1116-1120.
  11. Oberoi, T. K., Dogan, T., Hocking, J. C., Scholz, R. P., Mooz, J., Anderson, C. L., Karreman, C., Meyer zu Heringdorf, D., Schmidt, G., Ruonala, M., Namikawa, K., Harms, G. S., Carpy, A., Macek, B., Köster, R. W. & Rajalingam, K. (2012). IAPs regulate the plasticity of cell migration by directly targeting Rac1 for degradation. Embo J 31, 14-28.
  12. Konishi, H., Namikawa, K., Shikata, K., Kobatake, Y., Tachibana, T. & Kiyama, H. (2007). Identification of peripherin as a Akt substrate in neurons. J Biol Chem 282, 23491-23499.
  13. Kinoshita, K., Iimuro, Y., Fujimoto, J., Inagaki, Y., Namikawa, K., Kiyama, H., Nakajima, Y., Otogawa, K., Kawada, N., Friedman, S. L. & Ikeda, K. (2007). Targeted and regulable expression of transgenes in hepatic stellate cells and myofibroblasts in culture and in vivo using an adenoviral Cre/loxP system to antagonise hepatic fibrosis. Gut 56, 396-404.
  14. Kishibe, M., Bando, Y., Terayama, R., Namikawa, K., Takahashi, H., Hashimoto, Y., Ishida-Yamamoto, A., Jiang, Y. P., Mitrovic, B., Perez, D., Iizuka, H. & Yoshida, S. (2007). Kallikrein 8 is involved in skin desquamation in cooperation with other kallikreins. J Biol Chem 282, 5834-5841.
  15. Kitao, Y., Imai, Y., Ozawa, K., Kataoka, A., Ikeda, T., Soda, M., Namikawa, K., Kiyama, H., Stern, D. M., Hori, O., Wakamatsu, K., Ito, S., Itohara, S., Takahashi, R. & Ogawa, S. (2007). Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation. Hum. Mol. Genet. 16, 50-60.
  16. Murakami, K., Namikawa, K., Shimizu, T., Shirasawa, T., Yoshida, S. & Kiyama, H. (2006). Nerve injury induces the expression of EXT2, a glycosyltransferase required for heparan sulfate synthesis. Neuroscience 141, 1961-1969.
  17. Kawase, K., Nakamura, T., Takaya, A., Aoki, K., Namikawa, K., Kiyama, H., Inagaki, S., Takemoto, H., Saltiel, A. R. & Matsuda, M. (2006). GTP hydrolysis by the Rho family GTPase TC10 promotes exocytic vesicle fusion. Dev. Cell 11, 411-421.
  18. Namikawa, K., Murakami, K., Okamoto, T., Okado, H. & Kiyama, H. (2006). A newly modified SCG10 promoter and Cre/loxP-mediated gene amplification system achieve highly specific neuronal expression in animal brains. Gene Ther. 13, 1244-1250.
  19. Namikawa, K., Okamoto, T., Suzuki, A., Konishi, H. & Kiyama, H. (2006). Pancreatitis-associated protein-III is a novel macrophage chemoattractant implicated in nerve regeneration. J Neurosci 26, 7460-7467.
  20. Maeda, M., Namikawa, K., Kobayashi, I., Ohba, N., Takahara, Y., Kadono, C., Tanaka, A. & Kiyama, H. (2006). Targeted gene therapy toward astrocytoma using a Cre/loxP-based adenovirus system. Brain Res. 1081, 34-43.
  21. Konishi, H., Namikawa, K. & Kiyama, H. (2006). Annexin III implicated in the microglial response to motor nerve injury. Glia 53, 723-732.
  22. Inagaki, Y., Kushida, M., Higashi, K., Itoh, J., Higashiyama, R., Hong, Y. Y., Kawada, N., Namikawa, K., Kiyama, H., Bou-Gharios, G., Watanabe, T., Okazaki, I. & Ikeda, K. (2005). Cell type-specific intervention of transforming growth factor beta/Smad signaling suppresses collagen gene expression and hepatic fibrosis in mice. Gastroenterology 129, 259-268.
  23. Namikawa, K., Fukushima, M., Murakami, K., Suzuki, A., Takasawa, S., Okamoto, H. & Kiyama, H. (2005). Expression of Reg/PAP family members during motor nerve regeneration in rat. Biochem. Biophys. Res. Commun. 332, 126-134.
  24. Inagaki, Y., Kushida, M., Higashi, K., Itoh, J., Higashiyama, R., Hong, Y. Y., Saika, S., Ikeda, K., Yamanaka, O., Sato, M., Muragaki, Y., Ohnishi, Y., Ooshima, A., Nakajima, Y., Namikawa, K., Kiyama, H., Flanders, K. C. & Roberts, A. B. (2004). Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice. Lab Invest 84, 1259-1270.
  25. Okamoto, T., Namikawa, K., Asano, T., Takaoka, K. & Kiyama, H. (2004). Differential regulation of the regulatory subunits for phosphatidylinositol 3-kinase in response to motor nerve injury. Brain Res Mol Brain Res 131, 119-125.
  26. Maeda, M., Ohba, N., Nakagomi, S., Suzuki, Y., Kiryu-Seo, S., Namikawa, K., Kondoh, W., Tanaka, A. & Kiyama, H. (2004). Vesicular acetylcholine transporter can be a morphological marker for the reinnervation to muscle of regenerating motor axons. Neurosci Res 48, 305-314.
  27. Matsuzaki, H., Namikawa, K., Kiyama, H., Mori, N. & Sato, K. (2004). Brain-derived neurotrophic factor rescues neuronal death induced by methamphetamine. Biol Psychiatry 55, 52-60.
  28. Suzuki, Y., Nakagomi, S., Namikawa, K., Kiryu-Seo, S., Inagaki, N., Kaibuchi, K., Aizawa, H., Kikuchi, K. & Kiyama, H. (2003). Collapsin response mediator protein-2 accelerates axon regeneration of nerve-injured motor neurons of rat. J. Neurochem.86, 1042-1050.
  29. Osaka, H., Wang, Y. L., Takada, K., Takizawa, S., Setsuie, R., Li, H., Sato, Y., Nishikawa, K., Sun, Y. J., Sakurai, M., Harada, T., Hara, Y., Kimura, I., Chiba, S., Namikawa, K., Kiyama, H., Noda, M., Aoki, S. & Wada, K. (2003). Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron. Hum. Mol. Genet. 12, 1945-1958.
  30. Nakagomi, S., Suzuki, Y., Namikawa, K., Kiryu-Seo, S. & Kiyama, H. (2003). Expression of the activating transcription factor 3 prevents c-Jun N-terminal kinase-induced neuronal death by promoting heat shock protein 27 expression and Akt activation. J Neurosci 23, 5187-5196.
  31. Aoki, S., Su, Q., Li, H., Nishikawa, K., Ayukawa, K., Hara, Y., Namikawa, K., Kiryu-Seo, S., Kiyama, H. & Wada, K. (2002). Identification of an axotomy-induced glycosylated protein, AIGP1, possibly involved in cell death triggered by endoplasmic reticulum-Golgi stress. J Neurosci 22, 10751-10760.
  32. Honma, M., Namikawa, K., Mansur, K., Iwata, T., Mori, N., Iizuka, H. & Kiyama, H. (2002). Developmental alteration of nerve injury induced glial cell line-derived neurotrophic factor (GDNF) receptor expression is crucial for the determination of injured motoneuron fate. J. Neurochem. 82, 961-975.
  33. Iwata, T., Namikawa, K., Honma, M., Mori, N., Yachiku, S. & Kiyama, H. (2002). Increased expression of mRNAs for microtubule disassembly molecules during nerve regeneration. Brain Res Mol Brain Res 102, 105-109.
  34. Yamaguchi, A., Tamatani, M., Matsuzaki, H., Namikawa, K., Kiyama, H., Vitek, M. P., Mitsuda, N. & Tohyama, M. (2001). Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J Biol Chem 276, 5256-5264.
  35. Takahashi, H., Honma, M., Ishida-Yamamoto, A., Namikawa, K., Miwa, A., Okado, H., Kiyama, H. & Iizuka, H. (2001). In vitro and in vivo transfer of bcl-2 gene into keratinocytes suppresses UVB-induced apoptosis. Photochem. Photobiol. 74, 579-586.
  36. Takahashi, H., Honma, M., Ishida-Yamamoto, A., Namikawa, K., Kiyama, H. & Iizuka, H. (2001). Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway. J Biol Chem 276, 36632-36638.
  37. Matsuzaki, H., Tamatani, M., Yamaguchi, A., Namikawa, K., Kiyama, H., Vitek, M. P., Mitsuda, N. & Tohyama, M. (2001). Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades. Faseb J. 15, 1218-1220.
  38. Abe, K., Namikawa, K., Honma, M., Iwata, T., Matsuoka, I., Watabe, K. & Kiyama, H. (2001). Inhibition of Ras extracellular-signal-regulated kinase (ERK) mediated signaling promotes ciliary neurotrophic factor (CNTF) expression in Schwann cells. J. Neurochem. 77, 700-703.
  39. Iida, N., Namikawa, K., Kiyama, H., Ueno, H., Nakamura, S. & Hattori, S. (2001). Requirement of Ras for the activation of mitogen-activated protein kinase by calcium influx, cAMP, and neurotrophin in hippocampal neurons. J Neurosci 21, 6459-6466.
  40. Mitsuda, N., Ohkubo, N., Tamatani, M., Lee, Y. D., Taniguchi, M., Namikawa, K., Kiyama, H., Yamaguchi, A., Sato, N., Sakata, K., Ogihara, T., Vitek, M. P. & Tohyama, M. (2001). Activated cAMP-response element-binding protein regulates neuronal expression of presenilin-1. J Biol Chem 276, 9688-9698.
  41. Takano, R., Hisahara, S., Namikawa, K., Kiyama, H., Okano, H. & Miura, M. (2000). Nerve growth factor protects oligodendrocytes from tumor necrosis factor-alpha-induced injury through Akt-mediated signaling mechanisms. J Biol Chem 275, 16360-16365.
  42. Namikawa, K., Honma, M., Abe, K., Takeda, M., Mansur, K., Obata, T., Miwa, A., Okado, H. & Kiyama, H. (2000). Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J Neurosci 20, 2875-2886.
  43. Tsujino, H., Mansur, K., Kiryu-Seo, S., Namikawa, K., Kitahara, T., Tanabe, K., Ochi, T. & Kiyama, H. (1999). Discordant expression of c-Ret and glial cell line-derived neurotrophic factor receptor alpha-1 mRNAs in response to motor nerve injury in neonate rats. Brain Res Mol Brain Res 70, 298-303.
  44. Tanabe, K., Nakagomi, S., Kiryu-Seo, S., Namikawa, K., Imai, Y., Ochi, T., Tohyama, M. & Kiyama, H. (1999). Expressed-sequence-tag approach to identify differentially expressed genes following peripheral nerve axotomy. Brain Res Mol Brain Res 64, 34-40.
  45. Matsuzaki, H., Tamatani, M., Mitsuda, N., Namikawa, K., Kiyama, H., Miyake, S. & Tohyama, M. (1999). Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. J. Neurochem. 73, 2037-2046.
  46. Mansur, K., Iwahashi, Y., Kiryu-Seo, S., Su, Q., Namikawa, K., Yodoi, J. & Kiyama, H. (1998). Up-regulation of thioredoxin expression in motor neurons after nerve injury. Brain Res Mol Brain Res 62, 86-91.
  47. Toki, H., Namikawa, K., Su, Q., Kiryu-Seo, S., Sato, K. & Kiyama, H. (1998). Enhancement of extracellular glutamate scavenge system in injured motoneurons. J. Neurochem. 71, 913-919.
  48. Namikawa, K., Su, Q., Kiryu-Seo, S. & Kiyama, H. (1998). Enhanced expression of 14-3-3 family members in injured motoneurons. Brain Res Mol Brain Res 55, 315-320.
  49. Su, Q. N., Namikawa, K., Toki, H. & Kiyama, H. (1997). Differential display reveals transcriptional up-regulation of the motor molecules for both anterograde and retrograde axonal transport during nerve regeneration. Eur J Neurosci 9, 1542-1547.
  50. Morita, N., Namikawa, K. & Kiyama, H. (1995). Up-regulation of PKA RI alpha subunit mRNA in rat skeletal muscle after nerve injury. Neuroreport 6, 1050-1052.