Adult neurogenesis in the mouse models of ALS/FTLD

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09310
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: Ishigaki Shinsuke 名古屋大学, 医学系研究科, 寄附講座助教 (40378170)
• Co-Investigator(Kenkyū-buntansha): 渡辺 宏久 名古屋大学, 脳とこころの研究センター, 特任教授 (10378177) ; 祖父江 元 名古屋大学, 医学系研究科, 特任教授 (20148315)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: Adult neurogenesis / FTLD / ALS / tau / FUS / SFPQ

Outline of Final Research Achievements

Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T specific silencing resulted in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of ALS/FTLD.

Free Research Field

神経内科