Identification of novel genes closely related to Alzheimer's disease

Research Project

Project/Area Number	14580722
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	Nerve anatomy/Neuropathology
Research Institution	RIKEN (The Institute of Physical and Chemical Research)
Principal Investigator	OYAMA Fumitaka RIKEN (The Institute of Physical and Chemical Research), Brain Science Institute, Laboratory for Structural Neuropathology, Research Scientist, 構造神経病理研究チーム, 研究員 (40194641)
Co-Investigator(Kenkyū-buntansha)	原田彰広群馬大学, 生体調節研究所, 教授 (40251441)
Project Period (FY)	2002 – 2003
Project Status	Completed (Fiscal Year 2003)
Budget Amount *help	¥3,000,000 (Direct Cost: ¥3,000,000) Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000) Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Keywords	Alzheimer's disease / tau / tau deficient mouse / transcriptome / Gem GTPase / cell elongation activity
Research Abstract	Tau, one of the major microtubule-associated proteins, is involved in neuronal cell morphogenesis and axonal maintenance. Tau is also the major component of paired helical filaments found in the brain affected by Alzheimer's disease. To explore an as yet unidentified role of tau in vivo, 〜11,000 mRNAs were profiled from tau-deficient mouse brains, and compared with those from control brains at the same age. The expression of Gem GTPase, a small GTP binding protein of the ras superfamily, was significantly increased in the brain of tau-deficient mice at eight weeks of age. Because Gem GTPase is a negative regulator of the Rho-Rho kinase pathway for cytoskeletal regulation, this protein was transiently overexpressed in CHO cells that do not express tau. Overexpression of Gem GTPase induced a marked elongation of CHO cells, and simultaneous expression of tau eliminated this effect, although tau is not bound directly to Gem GTPase. This anti-elongation activity of tau was attributed to its microtubule (MT)-binding domain, and homologous domains of MAP2 and MAP4 exhibit similar antagonistic activities. Taken together, the present results indicate that the level of Gem GTPase and its cell elongation activity are modulated by tau, and suggest that tau may be involved in a Gem GTPase-mediated signal transduction pathway.