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【文摘发布】家族性阿尔茨海默病：特异性阻断
Authors: Omar Nelson1, Huiping Tu1, Tianhua Lei1, Mostafa Bentahir2, Bart de Strooper2 and Ilya Bezprozvanny1
1Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA. 2Center for Human Genetics, Katholieke Universiteit Leuven, and Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology, Leuven, Belgium.
Address correspondence to: Ilya Bezprozvanny, Department of Physiology, ND12.502, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040, USA. Phone: (214) 645-6017; Fax: (214) 645-6018; E-mail: Ilya.Bezprozvanny@UTSouthwestern.edu.
Resource:. Clin. Invest. 117:1230-1239 (2007). doi:10.1172/JCI30447
Abstract
Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by -secretase. Recently, we discovered that presenilins also function as passive ER Ca2+ leak channels. Here we used planar lipid bilayer reconstitution assays and Ca2+ imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca2+ leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants. We discovered that L166P, A246E, E273A, G384A, and P436Q FAD mutations in PS1 abolished ER Ca2+ leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca2+ leak function of PS1 in our experiments. We validated our findings in Ca2+ imaging experiments with primary fibroblasts obtained from an FAD patient possessing mutant PS1-A246E. Our results indicate that many FAD mutations in presenilins are loss-of-function mutations affecting ER Ca2+ leak activity. In contrast, none of the FTD-associated mutations affected ER Ca2+ leak function of PS1, indicating that the observed effects are disease specific. Our observations are consistent with the potential role of disturbed Ca2+ homeostasis in Alzheimer disease pathogenesis. 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领 Title: Familial Alzheimer disease–linked mutations specifically disrupt Ca2+ leak
function of presenilin 1
题目：家族性阿尔茨海默病：特异性阻断早老素1的钙离子通道功能的联合变异
Authors: Omar Nelson1, Huiping Tu1, Tianhua Lei1, Mostafa Bentahir2, Bart de Strooper2 and Ilya Bezprozvanny1
作者：Omar Nelson1, Huiping Tu1, Tianhua Lei1, Mostafa Bentahir2, Bart de Strooper2 and Ilya Bezprozvanny1
作者单位：1Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA. 2Center for Human Genetics, Katholieke Universiteit Leuven, and Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology, Leuven, Belgium.
Address correspondence to: Ilya Bezprozvanny, Department of Physiology, ND12.502,
University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040, USA. Phone: (214) 645-6017; Fax: (214) 645-6018; E-mail: Ilya.Bezprozvanny@UTSouthwestern.edu.
通讯作者：Ilya Bezprozvanny, Department of Physiology, ND12.502, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040, USA. Phone: (214) 645-6017; Fax: (214) 645-6018; E-mail: Ilya.Bezprozvanny@UTSouthwestern.edu.
Resource:. Clin. Invest. 117:1230-1239 (2007). doi:10.1172/JCI30447
来源：Clin. Invest. 117:1230-1239 (2007). doi:10.1172/JCI30447
Abstract
Mutations in presenilins are responsible for approximately 40% of all early-onset
familial Alzheimer disease (FAD) cases in which a genetic cause has been identified.
摘要：
早发性家族性阿尔茨海默病与遗传因素有关，其中40％的病例可有早老素的突变。
In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be
associated with the occurrence of frontal temporal dementia (FTD).
另外，许多早老素－1（PS1)突变与额颞叶失智症（FTD)的发病有关。
Presenilins are highly conserved transmembrane proteins that support cleavage of the
amyloid precursor protein by -secretase.
早老素是一类高度保守的跨膜蛋白，其通过分泌酶维持淀粉样前体蛋白（APP）的剪切。
Recently, we discovered that presenilins also function as passive ER Ca2+ leak channels. Here we used planar lipid bilayer reconstitution assays and Ca2+ imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca2+ leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants.
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作者:admin@医学,生命科学 2011-03-12 23:56
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