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

Cell. 2008 Jun 27;133(7):1149-61. doi: 10.1016/j.cell.2008.05.048.

Ute Dreses-Werringloer ¹, Jean-Charles Lambert, Valérie Vingtdeux, Haitian Zhao, Horia Vais, Adam Siebert, Ankit Jain, Jeremy Koppel, Anne Rovelet-Lecrux, Didier Hannequin, Florence Pasquier, Daniela Galimberti, Elio Scarpini, David Mann, Corinne Lendon, Dominique Campion, Philippe Amouyel, Peter Davies, J Kevin Foskett, Fabien Campagne, Philippe Marambaud

Affiliations

Affiliation

1 Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA.

PMID: 18585350 DOI: 10.1016/j.cell.2008.05.048

Abstract

Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (Abeta) 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 CA(2+) concentrations and Abeta levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA Receptor, and generates a large CA(2+) 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 Abeta levels by interfering with CALHM1-mediated CA(2+) permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral CA(2+) channel that controls Abeta levels and susceptibility to late-onset AD.

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