2011 Fiscal Year Final Research Report
The aggregation mechanisms of TDP-43 inclusion in neuronal cell
| Project/Area Number |
22700383
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | 財団法人東京都医学総合研究所 (2011)
Tokyo Metropolitan Organization for Medical Research (2010) |
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Principal Investigator |
YAMASHITA Makiko 財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 研究員 (00380668)
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| Project Period (FY) |
2010 – 2011
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| Keywords | TDP-43 / 神経変性疾患 / 凝集体形成阻害薬 |
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| Research Abstract |
TAR DNA binding protein of 43 kDa(TDP-43) is the major component of neuronal and glial inclusions aggregates characteristic of amyotrophic lateral sclerosis(ALS) and frontotemporal lobar degeneration with TDP-43-positive inclusions(FTLD-TDP). However, it remains to be clarified whether or not TDP-43 aggregates are toxic, and how abnormalities of TDP-43, such as aggregation, ubiquitination, hyperphosphorylation, fragmentation and loss of nuclear localization, lead to neuronal degeneration. We report here that proliferation of human neuroblastoma cell line SH-SY5Y with TDP-43 inclusions is strongly suppressed, compared to that of cells without the inclusions. Growth inhibition was especially strong in cells expressing a C-terminal fragment of TDP-43.Interestingly, the mechanism of cell growth inhibition by full-length TDP-43 involved arrest at the G2/M phase, whereas that by C-terminal fragment of TDP-43 did not. In TDP-43-expressing cells, RNA polymerase II and several transcription factors were found to be co-localized with TDP-43 aggregates. Furthermore, accumulation of RNA polymerase II in phosphorylated TDP-43 inclusions was detected in FTLD-TDP brains. These results suggest that abnormal TDP-43 inclusions itself is cytotoxic and lead to cellular dysfunction by recruiting normal transcription factors, resulting in growth arrest. Such transcriptional dysregulation may contribute to neuronal degeneration in TDP-43 proteinopathy.
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