A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβ levels, and Alzheimer's disease risk

被引：268

作者：

Dreses-Werringloer, Ute ^{[3
]}

Lambert, Jean-Charles ^{[4
]}

Vingtdeux, Valerie ^{[3
]}

Zhao, Haitian ^{[3
]}

Vais, Horia ^{[5
]}

Siebert, Adam ^{[5
]}

Jain, Ankit ^{[5
]}

Koppel, Jeremy ^{[3
]}

Rovelet-Lecrux, Anne ^{[6
]}

Hannequin, Didier ^{[6
]}

Pasquier, Florence ^{[7
]}

Galimberti, Daniela ^{[8
]}

Scarpini, Elio ^{[8
]}

Mann, David ^{[9
]}

Lendon, Corinne ^{[10
]}

Campion, Dominique ^{[6
]}

Amouyel, Philippe ^{[4
]}

Davies, Peter ^{[3
,11
]}

Foskett, J. Kevin ^{[5
]}

Campagne, Fabien ^{[1
,2
]}

Marambaud, Philippe ^{[3
,11
]}

机构：

[1] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA

[2] Cornell Univ, Weill Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulazix Alsau, New York, NY 10021 USA

[3] N Shore LIJ, Litwin Zucker Res Ctr Study Alzheimers Dis, Feinstein Inst Med Res, Manhasset, NY 11030 USA

[4] Univ Lille 2, Inst Pasteur, INSERM, U744, F-59019 Lille, France

[5] Univ Penn, Dept Phys, Sch Med, Philadelphia, PA 19104 USA

[6] Fac Med, INSERM, U614, F-76000 Rouen, France

[7] Univ Hosp, Dept Neurol, F-59037 Lille, France

[8] Univ Milan, Dept Neurol Sci, Dino Ferrari Ctr, IRCCS Osped Maggiore Policlin, I-20122 Milan, Italy

[9] Univ Manchester, Greater Manchester Neurosci Ctr, Salford M6 8HD, Lancs, England

[10] Queensland Inst Med Res, Mol Psychiat Grp, Brisbane, Qld 4006, Australia

[11] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA

来源：

CELL | 2008年 / 133卷 / 07期

关键词：

D O I：

10.1016/j.cell.2008.05.048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (A beta) peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca2+ concentrations and Ab levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca2+ conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3404 participants (allele-specific OR = 1.44, p = 2 x 10(-10)). We further found that the P86L polymorphism increases A beta levels by interfering with CALHM1-mediated Ca2+ permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca2+ channel that controls Ab levels and susceptibility to late-onset AD.

引用

页码：1149 / 1161

页数：13

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