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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Amino Acid Sequence
  • Amyloid beta-Peptides / metabolism*
  • Calcium / metabolism*
  • Calcium Channels
  • Cell Membrane / metabolism
  • Chromosomes, Human, Pair 10
  • Cytosol / metabolism
  • Female
  • Genetic Predisposition to Disease*
  • Genome, Human
  • Humans
  • Male
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism*
  • Middle Aged
  • Molecular Sequence Data
  • Phylogeny
  • Polymorphism, Genetic*
  • Sequence Alignment

Substances

  • Amyloid beta-Peptides
  • CALHM1 protein, human
  • Calcium Channels
  • Membrane Glycoproteins
  • Calcium