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Department of Biological Sciences
Molecular Neuroscience
Developmental Biology
Cellular Genetics
Molecular Genetics
Plant Development and Physiology
Cellular Biochemistry
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Photo Molecular Neuroscience Laboratory
Mechanisms that maintain the functional and structural integrity of neurons and their disruption in aging and disease

Our brains enable us to laugh, dance, love, and create. Brains are made up of networks of neuronal cells, which process and store huge amount of information. The vast majority of neurons that operate your brain last a lifetime and are not replaced and loss of neurons causes neurodegenerative diseases such as Alzheimerfs disease. How can we keep our brain functions during aging and reduce the risk of age-associated neurodegenerative diseases?

We tackle these questions with focuses on mitochondrial distribution in neurons and microtubule-binding protein tau, both of which play key roles in the pathogenesis of Alzheimerfs disease and other neurodegenerative diseases.
Our current research projects include (1) How tau gain toxicity in disease pathogenesis, (2) mechanisms underlying depletion of axonal mitochondria increase neuronal vulnerability, (3) age-dependent changes in local energy metabolism in neurons and risks of neurodegenerative diseases.
As experimental approaches, we use Drosophila models, molecular biology, biochemistry, behavioral analysis, gene expression analysis, and imaging.

We hope discoveries from this research enhance understanding of disease pathogenesis and contribute to increasing our healthspan.

As for Kanae Andofs publication before 2014, please see:
Asc Prof Kanae Ando e-mail
Ast Prof Akiko Asada e-mail
Ast Prof Taro Saito e-mail
Alzheimer's disease and other tauopathies
Misfolded tau protein is deposited in a group of neurodegenerative diseases called tauopathies, which include common forms of dementia such as AD and frontotemporal dementia. Abnormal accumulation of tau is believed to cause neuron loss in diseased brains, and modulation of this accumulation has been suggested as a strategy to delay or prevent disease onset and progression. However, it is not fully understood how tau accumulation starts in the disease brains and how it kills neurons. We aim to identify the posttranslational modifications in tau that trigger tau abnormality and elucidate the intracellular signaling cascade that leads to those changes by using cellular and animal models of disease (cultured neurons, transgenic flies and mouse) and molecular biology and biochemistry, imaging, histological analyses, and behavioral assays.

You can read an article about our latest paper here:
Search for a novel anti-brain aging strategy
Coming soon
You can read an article about our latest paper here:
Mitochondrial disease
Coming soon
Autism Spectrum Disorder
Autism spectrum disorder (ASD) is a developmental neurological disorder characterized by difficulties with social interaction and communication, and restricted and repetitive behavior. ASD affects 2-3% of the population, and it is believed that errors in the formation of neural circuits, such as precise parings between pre-and post-synaptic cells underlie disease pathogenesis.
Development of ASD can be influenced by genetic factors. Genetic models, such as Drosophila melanogaster, has been used to decipher the significance of these alterations. We use the Drosophila neuromuscular junction, a well-characterized model system for studies of structural and functional abnormalities induced by genetic perturbations, to analyze the role of genes linked to ASD in neuronal development.
Related Links
Recent Publications
  1. Saito T, Chiku T, Oka M, Wada-Kakuda S, Nobuhara M, Oba T, Shinno K, Abe S, Asada A, Sumioka A, Takashima A, Miyasaka T, Ando K.Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo.Hum Mol Genet. 2021 Jun 17:ddab162. doi: 10.1093/hmg/ddab162
  2. Oka M, Suzuki E, Asada A, Saito T, Iijima KM, Ando K. Increasing neuronal glucose uptake attenuates brain aging and promotes life span under dietary restriction in Drosophila. iScience. 2021 Jan 5;24(1):101979. doi: 10.1016/j.isci.2020.101979. PMID: 33490892; PMCID: PMC7806808.
  3. Oba, T., Saito, T., Asada, A., Shimizu, S., Iijima, KM, and Ando K. Microtubule Affinity Regulating Kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration. J Biol. Chem. J Biol Chem 2020 Oct 5;jbc.RA120.014420. doi: 10.1074/jbc.RA120.014420.
  4. Wei, R,, Sugiyama, A., Sato, Y., Nozumi, M., Nishino, H., Takahashi, M., Saito, T., Ando, K., Fukuda, M., Tomomura, M., Igarashi, M., Hisanaga, S. Isoform-dependent subcellular localization of LMTK1A and LMTK1B, and their roles in axon outgrowth and spine formation. J Biochem. 2020.
  5. Nishino H, Saito T, Wei R, Takano T, Tsutsumi K, Taniguchi M, Ando K, Tomomura M, Fukuda M, Hisanaga SI. (2019) The LMTK1-TBC1D9B-Rab11A cascade regulates dendritic spine formation via endosome trafficking. J Neurosci. 39, 9491-9502.
  6. Shimozawa, A., Fujita, Y., Kondo, K., Takimoto, Y., Terada, M., Sanagi, M., Hisanaga, S., Hasegawa, M, Effect of L-DOPA/benserazide on propagation of pathological -synuclein. Front. Neurosci. 13: 595. 2019.
  7. Sharma G, Huo A, Kimura T, Shiozawa S, Kobayashi R, Sahara N, Ishibashi M, Ishigaki S, Saito T, Ando K, Murayama S, Hasegawa M, Sobue G, Okano H, Hisanaga SI. (2019) Tau isoform expression and phosphorylation in marmoset brains. J Biol Chem. 294, 11433-11444.
  8. Furusawa, K., Takasugi, T., Chiu, Y-W., Hori, Y., Tomita, T., Fukuda, M., Hisanaga, S.
  9. CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway. J. Biol. Chem. 294:10886-10899. 2019
  10. Takahashi T, Minami S, Tsuchiya Y, Tajima K, Sakai N, Suga K, Hisanaga S, Ohbayashi N, Fukuda M, Kawahara H. Cytoplasmic control of Rab family small GTPases through BAG6. EMBO Rep. 20: e46794. 2019.
  11. Saito T, Oba T, Shimizu S, Asada A, Iijima KM, Ando K*. Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262. Hum Mol Genet. 2019. pii: ddz120.
  12. Takahashi M, Kobayashi Y, Ando K, Saito Y, Hisanaga SI. Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT1A receptor via phosphorylation. Biochem Biophys Res Commun. (2019);510(3):370-375.
  13. Chiku T., Hayashishita M., Saito T., Oka M., Shinno K., Ohtake Y., Shimizu S., Asada A., Hisanaga SI., Iijima KM, Ando, K*. (2018) S6K/p70S6K1 protects against tau-mediated neurodegeneration by decreasing the level of tau phosphorylated at Ser262 in a Drosophila model of tauopathy. Neurobiology of Aging, 3(71):255-264
  14. Sharma G, Huo A, Kimura T, Shiozawa S, Kobayashi R, Sahara N, Ishibashi M, Ishigaki S, Saito T, Ando K, Murayama S, Hasegawa M, Sobue G, Okano H, Hisanaga SI. (2018) J Biol Chem. 2019 Jun 5. pii: jbc.RA119.008415.
  15. Sekiya M, Wang M, Fujisaki N, Sakakibara Y, Quan X, Ehrlich ME, De Jager PL, Bennett DA, Schadt EE, Gandy S, Ando K, Zhang B, Iijima KM.Genome Med. 2018 Mar 29;10(1):26. doi: 10.1186/s13073-018-0530-9.Integrated biology approach reveals molecular and pathological interactions among Alzheimer's A42, Tau, TREM2, and TYROBP in Drosophila models.
  16. Kimura, T., Sharma, G., Ishiguro, K., Hisanaga, S. Phospho-tau bar code: analysis of phosphoisotypes of tau and its application to tauopathy. Fron. Mol. Neurosci., 12, 44, 2018.
  17. Tuerde, D., Kimura, T., Miyasaka, T., Furusawa, K., Shimozawa, A., Hasegawa, M., Ando, K., Hisanaga, SI. Isoform-independent and -dependent phosphorylation of microtubule-associated protein tau in mouse brain during postnatal development. J. Biol. Chem. 293: 1781-1793, 2018
  18. Furusawa, K., Asada, A., Urrutia, P., Gonzalez-Billault, C., Fukuda, M., Hisanaga, SI. Cdk5 Regulation of the GRAB-Mediated Rab8-Rab11 Cascade in Axon Outgrowth. J Neurosci. 37: 790-806., 2017.
  19. Akasaka-Manya, K., Kawamura, M., Tsumoto, H., Saitoh, Y., Shinobu Kitazume, S., Hatsuda, H., Miura, Y., Hisanaga, S., Murayama, S., Hashimoto, Y., Manya, H., Endo, T. Excess APP O-glycosylation by GalNAc-T6 decreases A production. J. Biochem. 161:99-111, 2017
  20. Krishnankutty, A., Kimura, T., Saito, T., Aoyagi, K., Asada, A., Takahashi, S., Ando, K., Ohara-Imaizumi, M., Ishiguro, K., Hisanaga, S. In vivo regulation of glycogen synthase kinase 3 activity in neurons and brains. Sci. Rep. Sci. Rep. 7, 8602, 2017.
  21. Sekiya, M., Maruko-Otake, A., Hearn, S., Sakakibara, Y., Fujisaki, N., Suzuki, E., Ando, K., Iijima, K. M.
  22. EDEM Function in ERAD Protects against Chronic ER Proteinopathy and Age-Related Physiological Decline in Drosophila. Dev Cell. 2017 Jun 19;41(6):652-664.e5. doi: 10.1016/j.devcel.2017.05.019.
  23. Oka, M., Iijima, K.M. and Ando, K.* (2017) Loss of synaptic mitochondria and dementia. Zikkennigaku, Yodosha (Japanese) Vol35, No12, p182-185, Yodosha
  24. Ando, K.*, Hearn, A., Suzuki, E., Maruko-Otake, A., Sekiya, M., and Iijima, K.M. (2015) Electron microscopy of the brains of Drosophila Models of Alzheimerfs disease. Neuromethods, DOI 10.1007/7657_2015_75, Springer
  25. Kimura, T., Hosokawa, T., Taoka, T., Tsutsumi, T., Ando, K., Ishiguro, K., Hosokawa, M., Hasegawa, M. and Hisanaga, S. (2016) Quantitative and combinatory determination of in situ phosphorylation of tau and its FTDP-17 mutants. Scientific Reports, ep 19;6:33479. doi: 10.1038/srep33479.
  26. Sharma, G., Tsutsumi, T., Saito, T., Asada, A., Ando, K., Tomomura, M., and Hisanaga, S. The kinase activity of endosomal kinase LMTK1A regulates its cellular localization and interactions with cytoskeletons. Genes to Cells, 2016 Oct;21(10):1080-1094. doi: 10.1111/gtc.12404.
  27. Ando, K*, Oka, M., Ohtake, Y., Hayashishita, M., Shimizu, S., Hisanaga, S., and Iijima, K.M.* (2016) Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated. Biochemical and Biophysical Research Communications, Volume 478, Issue 2, Pages 929–934
  28. Ando, K.*, Maruko-Otake, A., Ohtake, Y., Hayashishita, M., Sekiya, M., and Iijima, K. M. (2016) Stabilization of microtubule-unbound tau via tau phosphorylation at Ser262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and A42-induced tau toxicity. PLoS Genetics (12(3): e1005917. doi:10.1371/journal. pgen.1005917)
  29. 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)
  30. 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.@
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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
  36. Ueda, K. Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. J. Alz. Dis. 6: 435-442, 2004.
  37. 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.
  38. 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.
  39. Tomizawa, K., Sunada, S., Lu, Y-F., Oda, Y., Kinuta, M., Ohshima, T., Saito, T., Matsushita, M., Li, S-T., Moriwaki, A., Tsutsui, K.,
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. 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.
  47. 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.
  48. 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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