Laboratory for Structural Neuropathology
Laboratory Head
Nobuyuki NUKINA (M.D., Ph.D.)
The pathomechanism of neurodegenerative disorders are not fully elucidated yet. The responsible genes for hereditary neurodegenerative diseases have been identified by the genetic approach and many of those diseases showed the accumulation of their gene products in neurons. In Huntington disease and hereditary spinocerebellar ataxias, expanded polyglutamine accumulates and forms aggregates in neuronal nuclei. We are studying the pathological process in which the mutation induced the misfolding of the gene product and the misfolded gene product accumulates and induces neuronal degeneration using cell biological and structural biological approach. We are searching for the protecting factors and compounds for those pathological processes and chaperones and ubiquitin-proteasome pathway are important factors for the folding and degradation of misfolding proteins. The regulation of those factors are important for protecting those diseases. Our goal is to protect the conformational diseases induced by protein misfolding. In 2010, the following projects were reported. 1) We developed new gene therapy for degrading specifically expanded polyglutamine using chaperone mediated autophagy. 2)The newly identified polyQ binding transcriptional factor,Brn2 and its role in the neurodegeneration, was reported. 3)The effect of the ALS6 mutation on FUS/TLS function such as splicing and nuclear localization was reported
- Pathomechanism of polyglutamine diseases
- Development of therapy for polyglutamine diseases
- April 22, 2009
- Onset of polyglutamine disease progresses via accelerated fibrosing of proteins: Protein coupling likened to falling dominoes in newly proposed propagation mechanism
- October 20, 2008
- Clarification of the regulatory mechanism of 'amyloid-beta' production system, a cause of Alzheimer's disease, to develop new drugs for the disease.
- May 22, 2008
- Elucidation of the mechanism of regulation of enzymic activity which causes Alzheimer's disease, indicating pocket cavity size for capturing amyloid precursors and the presence of water molecules as key factors.
- March 10, 2008
- Huntington's disease takes protein prisoners
- Kino, Y., Washizu, C., Aquilanti, E., Okuno, M., Kurosawa, M., Yamada, M., Doi, H. & Nukina, N.
"Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations."
Nucleic. Acids Res. (2010) - Bauer, P.O., Goswami, A., Wong, H.K., Okuno, M., Kurosawa, M., Yamada, M., Miyazaki, H., Matsumoto, G., Kino, Y., Nagai, Y. & Nukina, N.
"Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein."
Nat. Biotechnol. 28, 256-263 (2010). - Furukawa, Y., Kaneko, K., Matsumoto, G., Kurosawa, M. & Nukina, N.
"Cross-seeding fibrillation of Q/N-rich proteins offers new pathomechanism of polyglutamine diseases."
J. Neurosci. 29, 5153-5162 (2009). - Sakurai, T., Kaneko, K., Okuno, M., Wada, K., Kashiyama, T., Shimizu, H., Akagi, T., Hashikawa, T. and Nukina, N.
"Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing."
J. Cell Biol. 183, 339-352 (2008). - Wong, H.K., Bauer, P.O., Kurosawa, M., Goswami, A., Washizu, C., Machida, Y., Tosaki, A., Yamada, M., Knopfel, T., Nakamura, T. and Nukina, N.
"Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism."
Hum. Mol. Genet. 17, 3223-3235 (2008). - Yamanaka, T., Miyazaki, H., Oyama, F., Kurosawa, M., Washizu, C., Doi, H. and Nukina, N.
"Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor."
EMBO J. 27, 827-839 (2008). - Doi, H., Okamura, K., Bauer, P.O., Furukawa, Y., Shimizu, H., Kurosawa, M., Machida, Y., Miyazaki, H., Mitsui, K., Kuroiwa, Y. and Nukina, N.:
"RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon 1 with expanded polyglutamine-expressing cells."
J. Biol. Chem. 283, 6489-6500 (2008). - Tanaka, M., Machida, Y., Niu, S., Ikeda, T., Jana, N-R., Doi, H., Kurosawa, M., Nekooki, M., and Nukina, N.:
"Trehalose effectively alleviates polyglutamine-mediated pathology in a transgenic mouse model of Huntington's disease"
Nat. Med. 10, 148-154 (2004). - Jana, N-R., Zemskov, E-A., Wang, G. and Nukina, N.
"Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release"
Hum. Mol. Genet. 10, 1049-1059 (2001). - Jana, N-R., Tanaka, M., Wang, G. nad Nukina, N.:
"Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity"
Hum. Mol. Genet. 9, 2009-2018 (2000).