Print Version
NOBUKI NAKANISHI, PH.D.
Associate Professor
Neurodegenerative Disease Research
858.795.5264 (phone)
858.795.5273 (fax)
nnakanishi@sanfordburnham.org
RESEARCH FOCUS, BIOGRAPHY, STAFF, PUBLICATION
Biography
Nobuki Nakanishi earned his Ph.D. from the University of Tokyo in 1987. He conducted his Ph.D. thesis research in the laboratory of Prof. Susumu Tonegawa from 1984 and 1988 at Massachusetts Institute of Technology Center for Cancer Research as a visiting scholar. From 1988-1993, he received postdoctoral training in the laboratory of Prof. Richard Axel at Columbia University, College of Physicians and Surgeons in New York as a Research Associate. Dr. Nakanishi was appointed Assistant Professor in the Department of Developmental Neurobiology at Harvard School where he conducted research 1993-1999. He was recruited the Sanford-Burnham Medical Research Institute in September 1999.
Selected Publications
Tu, S., Shin, Y., Zago, W.M., States, B.A., Eroshkin, A., Lipton, S.A., Tong, G.G., Nakanishi, N. Takusan: a large gene family that regulates synaptic activity. Neuron 55:69-85, 2007
Tong, G., Takahashi, H., Tu, S., Shin, Y., Talantova, M., Zago, W., Xia, P., Nie, Z., Goetz, T., Zhang, D., Lipton, S.A., Nakanishi, N. Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons. J. Neurophyisol. 99:122-32, 2008
Li, H., Radford, J.C., Ragusa, M.J., Shea, K.L., McKercher, S.R., Zaremba, J.D., Soussou, W., Nie, Z., Kang, Y.-J., Nakanishi, N., Okamoto, S.-I., Roberts, A.J., Schwarz, J.J., Lipton, S.A. Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci USA 105:9397-9402, 2008
Nakanishi, N., Tu, S., Shin, Y., Cui, J., Kurokawa, T., Zhang, D., Chen, H.-S.V., Tong, G., and Lipton, S.A. Neuroprotection by the NR3A Subunit of the NMDA Receptor. J Neuroscience 29:5260-5265, 2009
List of Publications via PubMed
(NIH National Library of Medicine)
Research Report
GLUTAMATE RECEPTORS AND NEURODEGENERATION
My laboratory focuses on the pathogenesis of neuronal cell death and a possible treatment using a gene that can regulate this process. The amino acid glutamate is the major excitatory synaptic transmitter in the brain. A class of glutamate-gated ion channels, responsive to the selective agonist N-methyl-D-aspartate (NMDA) is thought to play a crucial role in the neurotoxicity mediated by glutamate (termed excitotoxicity). Excitotoxicity, in turn, has been implicated in neuronal death in focal cerebral ischemia, epilepsy, CNS trauma, and several neurodegenerative disorders such as Huntington's disease, AIDS dementia, and Parkinsonism.
NR3A is a recently cloned glutamate-receptor subunit that shares high homology with NMDA-receptor subunits NR1 and NR2. Our data showed that NR3A protein is enriched in postsynaptic density (PSD) fractions of brain extracts from wild-type mice, and was co-immunoprecipitated with NR1 and NR2 subunits. In order to identify in vivo functions of NR3A, mutant (knock out) mice with targeted disruption of the NR3A gene have been generated in my laboratory. Whole-cell recordings with patch electrodes of acutely dissociated cortical neurons revealed that the mutant neurons exhibit larger NMDA-evoked current than wild-type cells.
Based on these data, we have proposed that NR3A is a novel regulatory subunit of NMDAR channels, and reduces NMDA-evoked current during the nomal development. We are now in the process of exploiting this unique feature of NR3A for a possible prevention of excitotoxicity by introducing this molecule as an exogenous reagent.
TAKUSAN: A LARGE GENE FAMILY THAT REGULATES SYNAPTIC ACTIVITY
We have characterized a species-specific gene family designated α-takusan (meaning ‘‘many’’ in Japanese). We initially identified a member of the family whose expression is upregulated in mice lacking the NMDAR subunit NR3A. We then isolated cDNAs encoding dozens of α-takusan variants from mouse brains. Most variants share an 130 aa long sequence, which contains the previously identified domain of unknown function 622 (DUF622) and is predicted to form coiled-coil structures. Single-cell PCR analyses indicate that one neuron can express multiple α-takusan variants and particular variants may predominate in certain cell types. Forced expression in cultured hippocampal neurons of two variants, α1 or α2, which bind either directly or indirectly to PSD-95, leads to an increase in PSD-95 clustering, dendritic spine density, GluR1 surface expression, and AMPAR activity. Conversely, treating cultured neurons with RNAi targeting a-takusan variants resulted in the opposite phenotype. Hence, a-takusan represents a large gene family that regulates synaptic activity.