TOP > Our research > Elucidation of molecular pathogenesis of neurodegenerative disorders.

Elucidation of molecular pathogenesis of neurodegenerative disorders.
Our research goal is to understand the molecular pathogenesis of neurodegenerative disorders and to develop essential therapies for the disorders. In 1999, we demonstrated that the gracile axonal dystrophy (gad) mouse is the first mammalian model of neurodegeneration with a defect in the ubiquitin system. The gad mouse lacks the expression of ubiquitin C-terminal hydrolase L1 (UCH-L1) that is a member of the deubiquitinating enzyme family. Unexpectedly, we found that UCH-L1 functions as an ubiquitin stabilizer as well. In the gad mouse, monoubiquitin level is decreased. The ubiquitin binding activity of UCH-L1 does not require its hydrolase activity. Thus, UCH-L1 is likely a multifunctional protein. We have found that the ubiquitin stabilization activity is involved in various biological aspects including neurogenesis, synaptic transmission and neurodegeneration.

I93M mutation of UCH-L1 is associated with PARK5 type of familiar Parkinson's disease. We recently reported UCH-L1 itself is modified by oxidative stress. Carbonyl-modified UCH-L1 shares some aberrant molecular properties with I93M UCH-L1. We believe this finding gives an important cue for understanding molecular pathogenesis of sporadic Parkinson disease.

We extend our research by collaborating various researchers outside neuroscience. For example, a collaborative team with neurology and neutron science found structural variations among wild-type and mutant UCH-L1 by SANS (small angled neutron scattering) analysis. Besides, students have joined our laboratory because our institute is an adjunctive university of Waseda University. This system works well and has helped to develop in silico drug screening of chemicals which target UCH-L3, an isozyme of UCH-L1.

Selected publications
  1. Saigoh, K., Wang, Y.-L., Suh, J.G., et al., Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mouse. Nature Genet., 23, 47-51, 1999
  2. Nishikawa, K., Li, H., Kawamura, R., et al. Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants., Biochem. Biophys. Res. Comm., 304, 176-183, 2003.
  3. Osaka, H., Wang, Y.L., Takada, K., et al. Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neurons. Hum. Mol. Genet., 12, 1945-1958, 2003
  4. Liu, W., Goto, J., Wang, Y.L., Murata, M., Wada, K.and Kanazawa, I. Specific inhibition of Huntington's disease gene expression by siRNAs in cultured cells. Proc. Japan Acad., 79, SerB, 293-298, 2003
  5. Harada, T., Harada, C., Wang, Y.L., et al. Role of ubiquitin carboxy terminal hydrolase-L1 in neural cell apoptosis induced by ischemic retinal injury in vivo. Am. J. Pathol., 164, 59-64, 2004
  6. Kwon, J., Wang, Y.L., Setsuie, R., et al.. Two closely related ubiquitin C-terminal hydrolase isozymes function as reciprocal modulators of germ cell apoptosis in cryptorchid testes. Am. J. Pathol., 165, 1367-1374, 2004.
  7. Manago, Y., Kanahori, Y., Shimada, A., Sato, A., Amano, T., Sato, Y., Setsuie, R., Sakurai, M., Aoki, S., Wang, Y.L., Osaka, H., Wada, K. and Noda, M. Potentiation of ATP-induced currents due to the activation of P2X receptors by ubiquitin carboxy-terminal hydrolase L1. J. Neurochem., 92, 1061-1072, 2005
  8. Wang, Y.L., Liu, W., Wada, E., Murata, M., Wada, K. Kanazawa, I., Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA. Neurosci. Res., 53, 241-249, 2005
  9. Naito S, Mochizuki H, Yasuda T, Mizuno Y, Furusaka M, Ikeda S, Adachi T, Shimizu HM, Suzuki J, Fujiwara S, Okada T, Nishikawa K, Aoki S, Wada K. Characterization of multimetric variants of ubiquitin carboxyl-terminal hydrolase L1 in water by small-angle neutron scattering. Biochem Biophys Res Commun. 339, 717-725, 2006
  10. Sakurai, M., Ayukawa, K., Setsuie, R., Nishikawa, K., Hara, Y., Ohashi, H., Nishimoto, M., Abe, T., Kudo, Y., Sekiguchi, M., Sato, Y, Aoki, S., Noda, M., and Wada, K. Ubiquitin C-terminal hydrolase L1 regulates the morphology of neural progenitor cells and modulates their differentiation. J. Cell Sci., 119(Pt1), 162-171, 2006
  11. Sano, Y., Furuta, A., Setsuie, R., Kikuchi, H., Wang, Y.L., Sakurai, M., Kwon, J., Noda, M., and Wada, K. Photoreceptor cell apoptosis in the retinal degeneration of Uchl3 deficient mice. Am. J. Pathol., 169, 132-141, 2006
  12. Kabuta, T., Suzuki, Y. and Wada, K. Degradation of amyotrophic lateral sclerosis-linked mutant SOD1 proteins by macroautophagy and the proteasome. J. Biol. Chem., 281, 30524-30533, 2006
  13. Setsuie, R., Wang, Y.L., Mochizuki, H., Osaka, H., Hayakawa, H., Ichihara, N., Li, H., Furuta, A., Sano, Y., Sun, Y.J., Kowan, J., Kabuta, T., Yoshimi, K., Aoki, S., Mizuno, Y., Noda, M. and Wada, K. Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant. Neurochem. Int., 50, 119-129, 2007
  14. Setsuie, R. Wada, K. The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem. Int., 52, 105-111, 2007. Review. Epub ahead of print, 2007 May 24
  15. Hirayama, K., Aoki, S., Nishikawa, K., Matsumoto, T., Wada, K. Identification of novel chemical inhibitors for ubiquitin C-terminal hydrolase-L3 by virtual screening. Bioorgan. Med. Chem 15, 6810-6818, 2007 2007 Aug 19; [Epub ahead of print]
  16. Sakurai, M., Sekiguchi, M., Zushida, K., Yamada, K., Nagamine, S., Kabuta, T. Wada, K. Reduction of memory in passive avoidance l;earning, exploratory behavior and synaptic plasticity in mice with a spontaneous deletion in the ubiquitin C-terminal hydrolase L1 gene. Eur. J. Neurosci., 27, 691-701, 2008
  17. Kabuta, T., Setsuie, R., Mitsui, T., Kinugawa, A., Sakurai, M., Aoki, S., Uchida, K., Wada, K. Aberrant molecular properties shared by familial Parkinson's disease-aasociated mutant UCH-L1 and carbonyl-modified UCH-L1. Hum. Mol. Genet., 2008 Feb 4; [Epub ahead of print]

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