Autoreguation of TDP-43 in ALS

2015 Fiscal Year Final Research Report

• Project/Area Number: 25253065
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Niigata University
• Principal Investigator: Nishizawa Masatoyo 新潟大学, 脳研究所, 教授 (80198457)
• Co-Investigator(Kenkyū-buntansha): ONODERA Osamu 新潟大学, 脳研究所, 教授 (20303167) ; ISHIHARA Tomohiko 新潟大学, 脳研究所, 助教 (70612232) ; KAKITA Akiyoshi 新潟大学, 脳研究所, 教授 (80281012) ; SATO Toshiya 北里大学, 医学部, 助教 (90359703)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 筋萎縮性側索硬化症

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. We show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons; especially neurons with mislocalized TDP-43; the amount of TARDBP mRNA is increased in the cytoplasm. Our observations suggests that that the absence of nuclear TDP-43 induces an abnormal autoregulation.

Free Research Field

神経内科学