Distinct pathways leading to cellular dysfunction by TDP-43
| Project/Area Number |
24700370
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | National Cancer Center Japan (2014)
Tokyo Metropolitan Institute of Medical Science (2012-2013) |
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Principal Investigator |
YAMASHITA Makiko 独立行政法人国立がん研究センター, 研究所, 研究員 (00380668)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 神経変性疾患 / TDP-43 / 凝集体形成 / ALS / FTLD-U / 神経細胞毒性 |
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| Outline of Final Research Achievements |
TDP-43 is the major component protein of inclusions in brains of patients with a ALS and FTLD-TDP. Here we report distinct cytotoxic effects by TDP-43 or its C-terminal fragment (CTF) using SH-SY5Y cells. When cells were overexpressed with full-length TDP-43 using a lentiviral system, striking cell death, caspase activation and growth arrest at G2/M phase were observed in these cells without any aggregate formation. In cells expressing TDP-43 CTF transiently, its aggregates were observed but significant cell death was not. Immunohistochemical analyses revealed that RNA polymerase II, Sp1 and CREB were co-localized with CTF aggregates, suggesting that recruitment of these factors to these aggregates cause the transcriptional dysregulation. Accumulation of RNA polymerase II with TDP-43 inclusions was also detected in FTLD-TDP brain. These suggest that different pathways leading to cellular dysfunction by TDP-43 may contribute to degeneration cascades in the onset of ALS and FTLD-TDP.
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Report
(4 results)
Research Products
(13 results)
