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Photo Molecular Neuroscience Laboratory
The brain is the central nervous system governing higher orders of neuronal functions such as learning, memory formation, motor and sensory functions, and so on. There are many unanswered questions regarding the brain. Various neuronal activities including differentiation, migration and neurite outgrowth of neurons, synaptic activity, neuronal aging and neuronal cell death, are regulated by a protein kinase called cyclin-dependent kinase 5 (Cdk5). We have been investigating the functions and regulation of Cdk5 in neurons to elucidate the molecular mechanisms underlying the complicated neuronal activities.
Faculty
Prof Shinichi Hisanaga e-mail
Asc Prof Kanae Ando e-mail
Ast Prof Akiko Asada e-mail
Ast Prof Taro Saito e-mail
Synaptic activity and Cdk5
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Localization of p35 Cdk5 activator in synaptic regions (Red). Stainings of synapse by actinin are shown below in green.
Synaptic transmission is a basic process in communication between neurons. Presynaptic neurons release neurotransmitters, which activate the receptors on the synaptic membrane of postsynaptic neurons, resulting in postsynaptic excitation. Cdk5 plays roles in both presynaptic and postsynaptic regulation. Cdk5 inhibits the release of the neurotransmitter in presynapse and maintains the resting state in postsynapse. Thus, Cdk5 appears to be a kind of suppressor that inhibits meaningless over-activation. However, it is not known how Cdk5 suppresses the activation. We are elucidating the regulation mechanism of Cdk5 activity and downstream pathway of Cdk5 in the postsynaptic region.
Mechanisms underlying mitochondrial distribution in the axon and neurodegeneration caused by loss of axonal mitochondria (Ando)
The brain processes information via networks made up of neurons. Neurons extend long axons for output, and axon terminals locate very far from the cell body. Mitochondria, powerhouses of the cell, are transported from cell body to the axon terminals and distribute to meet local energy demands. Reduction in the number and function of mitochondria in the axon terminals causes neuronal dysfunction and neurodegeneration, however, underlying mechanisms are not clear. We study the mechanisms that determine mitochondrial distribution and mechanisms underlie neuronal dysfunction and neurodegeneration caused by loss of axonal mitochondria by using Drosophila as a powerful genetic model system. So far, we reported that neurodegeneration caused by depletion of axonal mitochondria is mediated by the microtubule-associated protein tau, which is associated with a number of neurodegenerative diseases. Currently, our research focuses include (1) mechanisms that determine mitochondrial distribution in the axon, (2) signaling by which nucleus senses reduction in the number of functional mitochondria in the axon terminals, (3) mechanisms by which tau gains toxicity in pathological conditions. Since mitochondrial abnormality is observed in neurons in people suffering from neurodegenerative diseases such as Alzheimerfs disease, discoveries from this research may lead to development of a cure.
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Activation mechanism of Cdk5
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Glutamate, a major neurotransmitter in the central nervous system, inactivates the Cdk5 activity through degradation of activator p35 with proteasome.
Cdk5 is a neuron-specific protein kinase regulating many neuronal activities. We have already reported that Cdk5 is activated through stimulation of p35 synthesis by neurotrophic factors and that Cdk5 is inactivated through degradation of p35 activator with proteasome that is induced by neurotransmitters. There are two Cdk5 activator proteins, p35 and p39, in neurons. Compared to Cdk5-p35, which has been relatively well studied, nothing is known about Cdk5-p39. We are studying functional differences between Cdk5-p35 and Cdk5-p39 using an ectopic expression system in cultured cells, focusing on their cellular localization and membrane interactions.
Axonal dysfunctions and neurofilaments
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Electron micrographs of neurofilament made of wild type neurofilament (left) and CMT mutant neurofilament (right).
There are two types of processes in neurons, dendrites and axons. In particular, axons are thin and long processes, reaching more than 1 m. Neuronal signals are transferred along axons and their maintenance is very important for the proper functioning of sensory and motor activities. Neurofilaments are the most abundant cytoskeletal elements in axons. Neurofilaments are synthesized in the cell body and transported down to distal axons at a rate of about 0.5 – 1 mm/day. Mutation of neurofilament protein has recently been shown to disrupt the transport and cause peripheral neuropathy called Charcot-Marie-Tooth (CMT) disease. We are investigating the molecular mechanism by which mutations of neurofilament protein induce axonal atrophy.
Recent Publications
  1. Zhu, Y-S., Saito, T., Asada, A., Maekawa, S., and Hisanaga, S. Activation of latent cyclin-dependent kinase 5 (Cdk5)?p35 complexes by membrane dissociation. J. Neurochem. In press. (2005)
  2. Ohshima, T., Ogura, H., Tomizawa, K., Hayashi, K., Suzuki, H., Saito, T., Kamei, H., Nishi, A., Bibb, J. A., Hisanaga, S., Matsui, H., and Mikoshiba, K. Impairment of Hippocampal Long-Term Depression and Defective Spatial Learning and Memory in p35-/- Mice. J. Neurochem. In press.@
  3. Taniguchi, S., Suzuki, N., Masuda, M., Hisanaga, S., Iwatsubo, T., Goedert, M., and Hasegawa, M. Inhibition of heparin-induced tau filament formation by phenotiazine, polyphenols and porphyrins. J. Biol. Chem. 280, 7614-7623, 2005.
  4. Permana, S., Hisanaga, S., Nagatomo, Y., Iida, J., Hotani, H., and Itoh, T. J. Truncation of the projection domain of MAP4 (Microtubule-associated protein 4) leads to the attenuation of dynamic instability of microtubules. Cell Str. Funct. 29, 147-157, 2005.
  5. Wei, F-Y., Tomizawa, K., Ohshima, T., Asada, A., Saito, T., Nguyen, C., Bibb, J. A., Ishiguro, K., Kulkarni, A. B., Pant, H. C., Mikoshiba, K., Matsui, H., and Hisanaga. S. Control of Cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability. J. Neurochem. 93, 502-512, 2005.
  6. Hatanaka, Y., Hisanaga, S., Heizmann, C. W., and Murakami, F. Distinct migratory ehavior of early-and late-born neurons in the cerebral cortex. J. Comp. Neurol. 479, 1-14, 2004.
  7. Alim, M. A., Ma, Q-L., Takeda, K., Aizawa, T., Matsubara, M., Nakamura, M., Saito, T., Asada, A., Kaji, H., Yoshii, M., Hisanaga, S., and
  8. Ueda, K. Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. J. Alz. Dis. 6: 435-442, 2004.
  9. Uchida, A., Tashiro, T., Komiya, Y., Yorifuji, H., Kishimoto, T., and Hisanaga, S. Morphological and biochemical changes of neurofilaments in aged rat sciatic nerve axons. J. Neurochem. 88: 735-745, 2004.
  10. Hisanaga, S., and Saito, T. The regulation of Cdk5 kinase activity through the metabolism of p35 or p39 Cdk5 activator . Neurosignals 12: 221-229, 2004.
  11. Tomizawa, K., Sunada, S., Lu, Y-F., Oda, Y., Kinuta, M., Ohshima, T., Saito, T., Matsushita, M., Li, S-T., Moriwaki, A., Tsutsui, K.,
  12. Hisanaga, S., Mikoshiba, K., Takei, K., and Matsui, H. Cdk5/p35-dependent Phosphorylation of Amphiphysin I and Dynamin I: Critical Role in Clathrin-mediated Endocytosis of Synaptic Vesicles. J. Cell Biol., 163: 813-824, 2003.
  13. Honma, N., Asada, A., Takeshita, S., Enomoto, M., Yamakawa, E., Tsutsumi, K., Saito, T., Satoh, T., Itoh, H., Kaziro, Y., Kishimoto, T., and Hisanaga, S. Apoptosis-associated tyrosine kinase (AATYK) is a Cdk5 activator p35 binding protein. Biochem. Biophys. Res. Commun. 310: 398-404, 2003.
  14. Kawachi, A., Ichihara, K., Hisanaga, S., Iida, J., Toyota, H., Hotani, H., and Itoh, T. J. Different protofilament-dependence of the microtubule binding between MAP2 and MAP4. Biochem. Biophys. Res. Commun., 305: 72-78, 2003.
  15. Takahashi, S., Saito, T., Hisanaga, S., Pant, H. C., and Kulkarni, A.B. Tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules. J. Biol. Chem. 278: 10506-10515, 2003.
  16. Saito, T., Onuki, R., Fujita, Y., Kusakawa, G., Ishiguro, K., Bibb, J.A., Kishimoto, T., and Hisanaga, S. Developmental regulation of the proteolysis of the p35 Cdk5 activator by phosphorylation. J. Neurosci, 23: 1189-1197, 2003.
  17. Hashiguchi, M., Saito,T., Hisanaga, S., and Hashiguchi, T. Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau 40. J. Biol.Chem. 277: 44524-44530, 2002.
  18. Sasaki, T., Taoka, M., Ishiguro,K., Uchida,A., Saito,T., Isobe, T., and Hisanaga,S. In [1] <#_msocom_1> vivo and in vitro phosphorylation at Ser493 in the E-segment of neurofilament-H subunit by GSK3b. J. Biol. Chem. 277:36032-36039, 2002.
  19. Iida, J., Itoh, T. J., Hotani, H., Nishiyama, K., Murofushi, H., Bulinski, J. C., and Hisanaga, S. The projection domain of MAP4 suppresses the microtubule-bundling activity of the microtubule-binding domain. J. Mol. Biol. 320: 97-106, 2002.
  20. Alim, M.A., Hossain, M. S., Arima, K., Takeda, K., Izumiyama, Y., Nakamura, M., Kaji, H., Shinoda, T., Hisanaga, S., and Ueda, K. Tubulin seeds a-synuclein fibril formation. J. Biol. Chem. 272:2112-2117,2002.
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