***** seminarMLから情報転載 *****

8.20神経生化学セミナーのご案内その1/Neurochemistry Seminar Announcement

Title "Presenilins function as ER Ca2+ leak channels: implications for Alzheimer disease"
Lecturer: Ilya Bezprozvanny&s_comma; Ph.D. Affiliation: Dept. of Physiology&s_comma; Univ. of Texas Southwestern Medical Center&s_comma; Dallas&s_comma; TX 75390-9040&s_comma; USA

Time: August 20&s_comma; 2007 (Mon) 13:00~14:00
Place: Room 202 (Seminar Room 2)&s_comma; 2nd floor&s_comma; New Medical Research Building
Host: Haruhiko Bito&s_comma; Department of Neurochemistry (03-5841-3560)
Supported by Neuroscience Lecture Series&s_comma; Center for Integrated Brain Medical
Science&s_comma; a 21st Century COE Program from MEXT.

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative
disorder. Mutations in presenilins are responsible for approximately 40% of all
early onset familial Alzheimer’s disease (FAD) cases in which a genetic cause has been identified. In addition&s_comma; a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). FAD mutations and genetic deletions of presenilins have been linked with calcium (Ca2+) signaling abnormalities&s_comma; but mechanistic basis for these results has not been clearly determined.
Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by g-secretase. In our studies we discovered that in addition to acting as a g-secretase&s_comma; presenilins also function as passive endoplasmic reticulum alcium (Ca2+) leak channels. We demonstrate that wild type PS1 and PS2 proteins form low conductance divalent cation-permeable ion channels in planar lipid bilayers.
In experiments with PS1/2 double knockout (DKO) mouse embryonic fibroblasts (MEFs) we discovered that presenilins account for ~80% of passive Ca2+ leak from the endoplasmic reticulum. The ER Ca2+ leak function of presenilins is independent from their g-secretase function. In additional experiments we demonstrated that ER Ca2+ leak function of presenilins is impaired by M146V&s_comma; L166P&s_comma; A246E&s_comma; E273A&s_comma; G384A and P436Q FAD mutations in PS1 and N141I mutation in PS2.
In contrast&s_comma; FTD-associated mutations (L113P&s_comma; G183V and Rins352) did not appear to affect ER Ca2+ leak function of PS1 in our experiments&s_comma; indicating that the observed effects are disease-specific. Our data uncover a novel Ca2+
signaling function of presenilins and provide support to the potential role of disturbed Ca2+ homeostasis in AD pathogenesis.

[1] H Tu&s_comma; O Nelson&s_comma; A. Bezprozvanny&s_comma; Z. Wang&s_comma; S-F Lee&s_comma; Y-H Hao&s_comma; L Serneels&s_comma;
B De Strooper&s_comma; G Yu&s_comma; and I Bezprozvanny (2006). Presenilins form ER calcium leak
channels&s_comma; a function disrupted by familial Alzheimer’s disease-linked
mutations. Cell&s_comma; v 126&s_comma; pp 981-993.
[2] O Nelson&s_comma; H Tu&s_comma; T Lei&s_comma; M Bentahir&s_comma; B de Strooper&s_comma; and I Bezprozvanny
(2007) Familial Alzheimer’s disease-linked mutations specifically disrupt
calcium leak function of presenilin 1. Journal of Clinical Investigation&s_comma; vol.
117&s_comma; pp. 1230-1239.
脳神経医学専攻 神経生化学分野
〒113-0033 東京都文京区本郷7-3-1
e-mail: hbito@m.u-tokyo.ac.jp
Tel: 03-5841-3559 Fax: 03-3814-8154