Associate Professor (Cooperative Graduate School Program), Department of Biological Information
PhD 1999, Kyoto University
E-mail: motomasa(at)brain.riken.jp
Office: RIKEN Brain Science Institute, Room N504

Areas of Research: Neuroscience, Biophysics, Protein Chemistry, Proteomics/Genomics

Keywords: Neuropsychiatric disease, Local translation, Protein Misfolding, Amyloid, Yeast prion

Research interest:

 Many well-known neurodegenerative diseases such as Alzheimer's and Parkinson's diseases are caused by the misfolding and aggregation of a causative protein. In contrast, the underlying causes of neuropsychiatric diseases remain elusive. Recent genome-wide association studies have demonstrated that these diseases are complex in nature and rarely are caused by single gene mutations such as those involved in neurodegenerative diseases. We are interested to examine the molecular pathogenic mechanisms underlying these diseases using multiple approaches, combining both biophysical methods in conjunction with primary neuronal cultures and animal models to examine the functional deficits caused by protein misfolding both at the cellular level and at the whole animal level. We have recently reported that the exon1 fragment of huntingtin (causative protein of Huntington's disease) with an expanded polyglutamine (polyQ) tract misfolds into distinct amyloid conformations at different temperatures and demonstrated differential toxicity when introduced into mammalian cells. Importantly, we have also observed that huntingtin amyloids derived from different regions of the mouse brain had distinct conformations, which may underlie the increased susceptibility of striatal neurons to expanded polyQ huntingtin-mediated neurotoxicity.

 It had long been a mystery that strain differences occur both in mammalian and yeast prions. We previously reported how different prion strains arise due to the physical properties of the distinct prion (amyloid) conformations. Currently, we continue to explore yeast prion strains and transmission barriers via structural and genetic approaches. Through utilizing biophysical methods such as small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy, we are able to examine the structural details of the various conformational states that yeast prions such as Sup35 can assume. Through such efforts, we have recently reported that the prion domain of Sup35 (Sup35NM) forms reversible oligomers in a temperature-dependent manner. In the study, we have determined that distinct residues regulate amyloid core nucleation and growth. Specifically, we have shown that oligomer formation is mediated by non-native interactions outside of the amyloid core, which assembles Sup35NM monomers into close proximity such that the amyloid core region is free to interact to form amyloid fibrils.

Selected publications

  1. Nilsson P., Loganathan K., Sekiguchi M., Matsuba Y., Hui K., Tsubuki S., Tanaka M., Iwata N., Saito T., and Saido T.C.* Aβ secretion and plaque formation depend on autophagy. Cell Reports, 5, 61-69 (2013).
  2. Suzuki, G., Tanaka, M.* Active conversion to the prion state as a molecular switch for cellular adaptation to environmental stress. Bioessays, 35, 12-16 (2013).
  3. Suzuki, G. Shimazu, N., and Tanaka, M.* A Yeast Prion, Mod 5, Promotes Acquired Drug Resistance and Cell Survival Under Environmental Stress. Science 336, 355-359 (2012).
  4. Tanaka, M.* Tracking a toxic polyglutamine epitope. Nat. Chem. Biol. 7, 861-862 (2011).
  5. Foo, C.K., Ohhashi, Y., Kelly, M.J., Tanaka, M., and Weissman, J.S.* Radically Different Amyloid Conformations Dictate the Seeding Specificity of a Chimeric Sup35 Prion. J. Mol. Biol. 408, 1-8 (2011).
  6. Ohhashi, Y., Ito, K., Toyama, B.H., Weissman, J.S., and Tanaka M.* Differences in prion strain conformations result from non-native interactions in a nucleus. Nat. Chem. Biol. 6, 225-230 (2010).
  7. Nekooki-Machida, Y., Kurosawa, M., Nukina, N., Ito, K., Oda, T., and Tanaka, M.* Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proc. Natl. Acad. Sci. U. S. A., 106, 9678-9684(2009).
  8. Tanaka, M., Collins, S.R., Toyama, B.H., and Weissman, J.S.* The Physical Basis of How Prion Conformations Determine Strain Phenotypes. Nature, 442, 585-589 (2006).

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