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.
journal_name
Celljournal_title
Cellauthors
Dreses-Werringloer U,Lambert JC,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 JK,Campagne Fdoi
10.1016/j.cell.2008.05.048subject
Has Abstractpub_date
2008-06-27 00:00:00pages
1149-61issue
7eissn
0092-8674issn
1097-4172pii
S0092-8674(08)00751-4journal_volume
133pub_type
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