Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization.

• Project/Area Number: 15K08904
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: University of Fukui
• Principal Investigator: Shirafuji Norimichi 福井大学, 学術研究院医学系部門, 助教 (40529319)
• Co-Investigator(Kenkyū-buntansha): 濱野 忠則 福井大学, 学術研究院医学系部門, 准教授 (40334817)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ホモシステイン / タウ蛋白 / 神経原線維変化 / タウオパチー / サルコシル不溶性画分のタウ蛋白 / 高ホモシステイン血症 / カスパーゼ

Outline of Final Research Achievements

Hcy activated glycogen synthase kinase 3, a major tau phosphokinase, and inactivated protein phosphatase 2A, a main tau phosphatase. Hcy exhibited cytotoxic effects associated with enhanced activation of caspase. Truncation of tau in the C-terminus, the cleavage site of caspase3 (i.e., D421, detected by the TauC3 antibody) also was increased. Total tau, phosphorylated tau, as well as C-terminal cleaved tau were increased in the sarkosyl insoluble tau fraction. Hcy also increased the level of tau oligomers, as indicated by the tau oligomer complex 1 (TOC1) antibody that specifically identifies oligomeric tau species, in the tris insoluble, sarkosyl soluble fraction.The levels of TOC1-positive oligomeric tau were increased in brain lysate from HHCy mice.
These observations suggest that Hcy increases the levels of phosphorylated tau as well as truncated tau species via caspase3 activation, and enhanced tau oligomerization and aggregation.

Research Products

• [Journal Article] Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization. (2018)
  • Author(s): Norimichi Shirafuji,Tadanori Hamano
  • Journal Title: Molecular Sciences Volume: 19 Pages: 891-914
  • Peer Reviewed / Open Access
• [Journal Article] A case of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody-positive paraneoplastic necrotizing myopathy associated with advancee gastric cancer that responded to intravenous immunoglobulin therapy. (2017)
  • Author(s): Yamaguchi T,Matsunaga A,Ikawa M,Shirafuji N
  • Journal Title: Rinsho Shinkeigaku Volume: 28 Pages: 118-123
  • Open Access
• [Journal Article] Pioglitazone prevents tau oligomerization. (2016)
  • Author(s): Hamano T, Shirafuji N, Makino C, Yen SH, Kanaan NM, Ueno A, Suzuki J, Ikawa M, Matsunaga A, Yamamura O, Kuriyama M, Nakamoto Y.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 3 Pages: 1035-1042
  • DOI: 10.1016/j.bbrc.2016.08.016
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Homocysteine Increases Tau Phosphorylation Truncation and Oligomerization. (2018)
  • Author(s): Norimichi Shirafuji
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] HYPOPERFUSION-INDUCED TAU HYPERPHOSPHORYLATION EXTENDS TO THE NON-HYPOPERFUSED AREA IN MOUSE BRAIN. (2016)
  • Author(s): Fujita,Y.,Hamano,T., Shirafuji,N.
  • Organizer: Alzheimer's Association International Conference (AAIC) 2016
  • Place of Presentation: Tronto, Canada
  • Int'l Joint Research