Establishment of TDP-43 C-terminal deficient mice using zinc finger nuclease and application to the model for amyotrophic lateral sclerosis

2015 Fiscal Year Final Research Report

• Project/Area Number: 25461271
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kitasato University (2014-2015); Niigata University (2013)
• Principal Investigator: SATO TOSHIYA 北里大学, 医学部, 教授 (90359703)
• Co-Investigator(Kenkyū-buntansha): KODERA YOSHIO 北里大学, 理学部, 准教授 (60265733)
• Co-Investigator(Renkei-kenkyūsha): ONODERA OSAMU 新潟大学, 脳研究所, 教授 (20303167)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: ALS / TDP-43 / 疾患モデル

Outline of Final Research Achievements

To investigate the physiological functions of the C-terminal region (CTR) of TDP-43, we established eight lines of CTR deficient mice using zinc finger nuclease. Mutant TDP-43 mice carrying a deletion within 6 amino acids in the middle of CTR (A) appeared normal even in the homozygote, whereas homozygous mice carrying a large deletion of the N- (B; 262-348) or C-terminal (C; 345-414) half of CTR showed embryonic lethality. In the brains of heterozygous B or C mice, a comparable level of the truncated protein corresponding to the large deletion was observed only in B mice. The truncated TDP-43 was exclusively in the cytoplasm fraction, thus it could not show physiological function in the nucleus. These results show N-terminal half of CTR is essential for maintaining nuclear function of TDP-43, whereas C-terminal half of CTR is important for the protein stability.

Free Research Field

医歯薬学