A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk

Ute Dreses-Werringloer, 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 CampagnePhilippe Marambaud

Research output: Contribution to journalArticle

Abstract

Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-β (Aβ) 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 Aβ 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 × 10-10). We further found that the P86L polymorphism increases Aβ 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 Aβ levels and susceptibility to late-onset AD.

Original languageEnglish
Pages (from-to)1149-1161
Number of pages13
JournalCell
Volume133
Issue number7
DOIs
Publication statusPublished - Jun 27 2008

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Keywords

  • HUMDISEASE
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Dreses-Werringloer, U., Lambert, J. C., Vingtdeux, V., Zhao, H., Vais, H., Siebert, A., Jain, A., Koppel, J., Rovelet-Lecrux, A., Hannequin, D., Pasquier, F., Galimberti, D., Scarpini, E., Mann, D., Lendon, C., Campion, D., Amouyel, P., Davies, P., Foskett, J. K., ... Marambaud, P. (2008). A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk. Cell, 133(7), 1149-1161. https://doi.org/10.1016/j.cell.2008.05.048