2021/05/16 更新

写真a

イノウエ マサフミ
井上 雅文
INOE Masafumi
所属
脳研究所 特任助教
職名
特任助教
外部リンク

学位

  • 博士(エネルギー科学) ( 2010年3月   京都大学 )

研究分野

  • ナノテク・材料 / ナノバイオサイエンス

経歴

  • 新潟大学   脳研究所 生命科学リソース研究センター   特任助教

    2019年1月 - 現在

 

論文

  • Rapid chemical clearing of white matter in the post-mortem human brain by 1,2-hexanediol delipidation. 査読

    Inoue M, Saito R, Kakita A, Tainaka K

    Bioorganic & medicinal chemistry letters29 ( 15 ) 1886 - 1890   2019年8月

  • Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. 査読

    Ohnishi T, Yanazawa M, Sasahara T, Kitamura Y, Hiroaki H, Fukazawa Y, Kii I, Nishiyama T, Kakita A, Takeda H, Takeuchi A, Arai Y, Ito A, Komura H, Hirao H, Satomura K, Inoue M, Muramatsu S, Matsui K, Tada M, Sato M, Saijo E, Shigemitsu Y, Sakai S, Umetsu Y, Goda N, Takino N, Takahashi H, Hagiwara M, Sawasaki T, Iwasaki G, Nakamura Y, Nabeshima Y, Teplow DB, Hoshi M

    Proceedings of the National Academy of Sciences of the United States of America112 ( 32 ) E4465 - E4474   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1073/pnas.1421182112

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  • Structural Insight into an Alzheimer's Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR. 査読

    Parthasarathy S, Inoue M, Xiao Y, Matsumura Y, Nabeshima Y, Hoshi M, Ishii Y

    Journal of the American Chemical Society137 ( 20 ) 6480 - 6483   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/jacs.5b03373

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  • Phosphorylation regulates fibrillation of an aggregation core peptide in the second repeat of microtubule-binding domain of human tau 査読

    Masafumi Inoue, Shinji Kaida, Shun Nakano, Chiara Annoni, Eiji Nakata, Takashi Konno, Takashi Morii

    BIOORGANIC & MEDICINAL CHEMISTRY22 ( 22 ) 6471 - 6480   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Hyperphosphorylation of the microtubule-associated protein tau is believed to play a crucial role in the neurofibrillary tangles formation in Alzheimer's disease brain. In this study, fibril formation of peptides containing the critical sequences for tau aggregation VQIINK and a plausible serine phosphorylation site of tau at its C-terminal was investigated. All the peptides formed fibrils with the typical cross-beta structural core. However, stability of the fibrils was highly sensitive to the pH conditions for the phosphorylated VQIINK peptide, suggesting a regulatory role of phosphorylation for the amyloid-formation of tau. (C) 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.bmc.2014.09.032

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  • Positional Effects of Phosphorylation on the Stability and Morphology of Tau-Related Amyloid Fibrils 査読

    Masafumi Inoue, Takashi Konno, Kazuki Tainaka, Eiji Nakata, Hiro-o Yoshida, Takashi Morii

    BIOCHEMISTRY51 ( 7 ) 1396 - 1406   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    Hyperphosphorylated forms of tau protein are the main component of paired helical filaments (PHFs) of neurofibrillary tangles in the brain of Alzheimer's disease patients. To understand the effect of phosphorylation on the fibrillation of tau, we utilized tau-derived phosphorylated peptides. The V(306)QIVYK(311) sequence (PHF6) in the microtubule-binding domain is known to play a key role in the fibrillation of tau, and the short peptide corresponding to the PHF6 sequence forms amyloid-type fibrils similar to those generated by full-length tau. We focused on the amino acid residue located at the N-terminus of the PHF6 sequence, serine or lysine in the native isoform of tau, and synthesized the PHF6 derivative peptides with serine or lysine at the N-terminus of PHF6. Peptides phosphorylated at serine and/or tyrosine were synthesized to mimic the possible phosphorylation at these positions. The critical concentrations of the fibrillation of peptides were determined to quantitatively assess fibril stability. The peptide with the net charge of near zero tended to form stable fibrils. Interestingly, the peptide phosphorylated at the N-terminal serine residue exhibited remarkably low fibrillation propensity as compared to the peptide possessing the same net charge. Transmission electron microscopy measurements of the fibrils visualized the paired helical or straight fibers and segregated masses of the fibers or heterogeneous rodlike fibers depending on the phosphorylation status. Further analyses of the fibrils by the X-ray fiber diffraction method and Fourier transform infrared spectroscopic measurements indicated that all the peptides shared a common cross-beta structure. In addition, the phosphoserine-containing peptides showed the characteristics of beta-sandwiches that could interact with both faces of the beta-sheet. On the basis of these observations, possible protofilament models with four beta-sheets were constructed to consider the positional effects of the serine and/or tyrosine phosphorylations. The electrostatic intersheet interaction between phosphate groups and the amino group of lysine enhanced the lateral association between beta-sheets to compensate for the excess charge. In addition to the previously postulated net charge of the peptide, the position of the charged residue plays a critical role in the amyloid fibrillation of tau.

    DOI: 10.1021/bi201451z

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  • Two Distinct Amyloid beta-Protein (A beta) Assembly Pathways Leading to Oligomers and Fibrils Identified by Combined Fluorescence Correlation Spectroscopy, Morphology, and Toxicity Analyses 査読

    Satoko Matsumura, Keiko Shinoda, Mayumi Yamada, Satoshi Yokojima, Masafumi Inoue, Takayuki Ohnishi, Tetsuya Shimada, Kazuya Kikuchi, Dai Masui, Shigeki Hashimoto, Michio Sato, Akane Ito, Manami Akioka, Shinsuke Takagi, Yoshihiro Nakamura, Kiyokazu Nemoto, Yutaka Hasegawa, Hisayoshi Takamoto, Haruo Inoue, Shinichiro Nakamura, Yo-ichi Nabeshima, David B. Teplow, Masataka Kinjo, Minako Hoshia

    JOURNAL OF BIOLOGICAL CHEMISTRY286 ( 13 ) 11555 - 11562   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Nonfibrillar assemblies of amyloid beta-protein (A beta) are considered to play primary roles in Alzheimer disease (AD). Elucidating the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based therapies. However, these assemblies cannot be monitored in vivo, and there has been no reliable in vitro monitoring method at low protein concentration. We have developed a highly sensitive in vitro monitoring method using fluorescence correlation spectroscopy (FCS) combined with transmission electron microscopy (TEM) and toxicity assays. Using A beta labeled at the N terminus or Lys(16), we uncovered two distinct assembly pathways. One leads to highly toxic 10-15-nm spherical A beta assemblies, termed amylospheroids (ASPDs). The other leads to fibrils. The first step in ASPD formation is trimerization. ASPDs of similar to 330 kDa in mass form from these trimers after 5 h of slow rotation. Up to at least 24 h, ASPDs remain the dominant structures in assembly reactions. Neurotoxicity studies reveal that the most toxic ASPDs are similar to 128 kDa (similar to 32-mers). In contrast, fibrillogenesis begins with dimer formation and then proceeds to formation of 15-40-nm spherical intermediates, from which fibrils originate after 15 h. Unlike ASPD formation, the Lys(16)-labeled peptide disturbed fibril formation because the A beta(16-20) region is critical for this final step. These differences in the assembly pathways clearly indicated that ASPDs are not fibril precursors. The method we have developed should facilitate identifying A beta assembly steps at which inhibition may be beneficial.

    DOI: 10.1074/jbc.M110.181313

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  • Charge-Pairing Mechanism of Phosphorylation Effect upon Amyloid Fibrillation of Human Tau Core Peptide 査読

    Masafumi Inoue, Akiyoshi Hirata, Kazuki Tainaka, Takashi Morii, Takashi Konno

    BIOCHEMISTRY47 ( 45 ) 11847 - 11857   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    Phosphorylation of a fibrillogenic protein, human tau, is believed to play crucial roles in the pathogenesis of Alzheimer's disease. For elucidating molecular mechanisms of the phosphorylation effect on tau fibrillation, we synthesized a peptide, VQTVY(310)K (PHF6) and its phosphorylated derivative (PHF(6)pY). PHF6 is a partial peptide surrounding a plausible in vivo phosphorylation site Tyr310 and forms amyloid-type fibrils similar to those generated by full-length tau. Fibrillation of PHF6 and PHF6pY were studied by spectroscopic and microscopic methods, and the critical concentration of the fibrillation was determined for comparing the fibril stability. The results showed that the phosphorylation strongly influenced the fibrillation propensity of PHF6 by changing its dependency on pH and ionic strength. On the basis of the observations, we suggested that charged sites on the phosphate group and its electrostatic pairing with the neighboring charged residues were physical origins of the phosphorylation effect. To verify this charge-pairing mechanism, we conducted experiments using a series of PHF6 derivatives with non-native charge distributions. The electrostatic interaction in an intermolecular mode was also demonstrated by the system composed of two different peptide species, which found that fibrillation of nonphosphorylated PHF6 was drastically enhanced when a trace amount of phosphorylated PHF6 molecules coexisted. A simulation analysis utilizing crystal coordinates of the PHF6 fibril was also performed for interpreting the experimental results in a molecular level. The present study using the model peptide system gave us a microscopically insightful view on the roles of tau phosphorylation in amyloid-related diseases.

    DOI: 10.1021/bi8010994

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