| Project/Area Number |
21390333
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Psychiatric science
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TANAKA Toshihisa 大阪大学, 医学系・研究科, 講師 (10294068)
KUDO Takashi 大阪大学, 医学系・研究科, 准教授 (10273632)
MORIHARA Takashi 大阪大学, 医学系・研究科, 助教 (90403196)
|
|---|
| Project Period (FY) |
2009 – 2011
|
| Project Status |
Completed (Fiscal Year 2011)
|
| Budget Amount *help |
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2011: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
|
|---|
| Keywords | 老年精神医学 / アルツハイマー病 / 前頭側頭型認知症 / 神経原繊維変化 / タウ蛋白 / プロテアーゼ / リン酸化 / 神経原線維変化 |
|---|
| Research Abstract |
Tau protein is hyperphosphorylated, ubiquitinated and accumulated in FTDP-17 brains, however mechanisms of the accumulation is still unclear. To understand the involvement of proteases in metabolisms of tau protein, some of protease inhibitors were employed in cultured cells. Pulse-chase experiments revealed proteolysis of tau protein was attenuated when treated with puromycin. And increased tau protein levels were also observed in cells treated with siRNA to puromycin-sensitive aminopeptidase(PSA) for inhibition of its expression. Those data suggest that PSA is a protease which regulates proteolysis of tau predominantly in cells. The protein metabolism of tau containing FTDP-17 mutations was also investigated employing pulse-chase experiments and attenuated proteolysis of tau was observed in the cells transfected with the mutant tau. Phosphorylation of tau at Thr231, Ser396 and Ser409 was increased in the cells transfected with V337M, R406W, and R406W mutant tau gene, respectively. These results suggest that attenuated proteolysis of FTDP-17 mutant tau might be explained by the increased phosphorylation levels resulting in resistance to proteolysis. Furthermore, in cells treated with fumagilin, an inhibitor to methionine aminopeptidase, tau protein with N-terminal methionine increased similar to puromicin-treated cells, suggesting that aminoterminal processing of tau protein is important for tau degradation.
|
