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.

A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk / U. Dreses-Werringloer, J.C. Lambert, V. Vingtdeux, H. Zhao, H. Vais, A. Siebert, A. Jain, J. Koppel, A. Rovelet-Lecrux, D. Hannequin, F. Pasquier, D. Galimberti, E. Scarpini, D. Mann, C. Lendon, D. Campion, P. Amouyel, P. Davies, J.K. Foskett, F. Campagne. - In: CELL. - ISSN 0092-8674. - 133:7(2008), pp. 1149-1161.

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

D. Galimberti;E. Scarpini;
2008

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.
Settore MED/26 - Neurologia
2008
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/42130
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