| Project/Area Number |
22240039
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
YOKOTA Takanori 東京医科歯科大学, 大学院・医歯学総合研究科, 特別研究教授 (90231688)
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| Co-Investigator(Kenkyū-buntansha) |
UCHIHARA Toshiki 公益財団法人東京都医学総合研究所, 東京 都神経科学総合研究所, 副参事研究員 (10223570)
URUSHIDANI Makoto 滋賀医科大学, 分子神経科学研究センター, 准教授 (60332326)
KIMURA Nobuyuki 独立行政法人医薬基盤研究所, 霊長類医科 学研究センター, 研究員 (80392330)
KUWABARA Satoshi 千葉大学, 大学院・医学研究院, 教授 (70282481)
HIGUCHI Osamu 独立行政法人国立病院機構長崎川棚医療センター, 免疫ゲノム医科学研究室, 室長 (50361720)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥49,790,000 (Direct Cost: ¥38,300,000、Indirect Cost: ¥11,490,000)
Fiscal Year 2012: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
Fiscal Year 2011: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000)
Fiscal Year 2010: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
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| Keywords | 神経変性疾患 / 筋萎縮性側索硬化症 / 動物モデル / TDP-43 / AAV / 軸索電流 / エクソソーム / ALS / サル / 前角運動神経細胞 / リン酸化 / Betz巨細胞 / 運動ニューロン / Cystatin C / サルモデル / 外側核 / リン酸化ニューロフィラメンド / SHSY-5Y |
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| Research Abstract |
TDP-43 was found to be a major component of abnormal aggregation in the motoneuron in sporadic ALS. We injected an AAV vector expressing human wild-type TDP-43 to the spinal cord in non-human primate, cynomolgus. These monkeys developed progressive motor weakness and muscle atrophy. They also showed regional cytoplasmic TDP-43 mislocalization with loss of nuclear TDP-43 staining, reminiscent of the spinal cord pathology of patients with ALS. TDP-43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that TDP-43 mislocalization leads to alpha-motoneuron degeneration. This model can privide a valuable tool for studying the pathogenesis of sporadic ALS.
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