2012 Fiscal Year Final Research Report
Investigation of effect of TDP-43 aggregation on translational control
| Project/Area Number |
23791008
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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 |
Neurology
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| Research Institution | 公益財団法人東京都医学総合研究所 (2012)
Tokyo Metropolitan Organization for Medical Research (2011) |
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Principal Investigator |
HIGASHI Shinji 公益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 (30365647)
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| Co-Investigator(Renkei-kenkyūsha) |
AKIYAMA Haruhiko 公益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, 参事研究員 (20231839)
WADA Keiji 独立行政法人国立精神, 神経医療センター, 疾病研究第4部.部長 (70250222)
KABUTA Tomohiro 独立行政法人国立精神, 神経医療センター, 疾病研究第4部.室長 (70535765)
NAGAI Yoshitaka 独立行政法人国立精神, 神経医療センター, 疾病研究第4部.室長 (60335354)
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| Project Period (FY) |
2011 – 2012
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| Keywords | 神経科学 / 神経変性疾患 / 筋萎縮性側索硬化症 / 前頭側頭型認知症 / TDP-43 / ストレス顆粒 / 酸化ストレス / 細胞死 |
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| Research Abstract |
TDP-43 has emerged as an important contributor to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Polysome profiling analysis revealed that oxidative stress caused the association of TDP-43 with stalled ribosomes via binding to mRNA. When the cells were exposed to short-term/non-lethal stress, TDP-43 associating with ribosomes localized to stress granules (SGs) and this association was transient. In contrast, when the cells were exposed to long-term/sublethal stress, TDP-43 was excluded from SGs and shifted to the heavy fractions independent of any binding to mRNA. In these severely stressed cells, TDP-43 was insolubilized and phosphorylated. In TDP-43-silenced cells, stalled mRNA and poly (A)+ RNA stability was disturbed and cytotoxicity increased under sublethal stress.
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