Abstract
Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer’s disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca2+-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.
Highlights
Key neuronal processes including neurotransmission, synaptic plasticity, learning and memory are regulated by intracellular calcium (Ca2+) levels, and alterations in Ca2+ dynamics have dramatic consequences in signaling cascades, cytoskeleton modifications, synaptic function, and neuronal survival [1,2]
Identification of Calcium Homeostasis Modulator 1 (CALHM1) mutations Mutation screening of the CALHM1 gene in early-onset AD (EOAD) patients disclosed a heterozygous G to A transition (c.G989A), which results in the replacement of a glycine to aspartic acid at codon 330 (p.G330D) in a Spanish patient
To rule out that the p.G330D was a common variant within the Spanish population, 384 healthy additional controls belonging to the same geographic ancestry were subjected to RFLP analysis
Summary
Key neuronal processes including neurotransmission, synaptic plasticity, learning and memory are regulated by intracellular calcium (Ca2+) levels, and alterations in Ca2+ dynamics have dramatic consequences in signaling cascades, cytoskeleton modifications, synaptic function, and neuronal survival [1,2]. A novel Ca2+ conducting channel, named CALHM1 (for calcium homeostasis modulator 1), has been proposed as a key modulator of intracellular Ca2+ homeostasis [17,18,19]. Characterization of this protein disclosed a multipass, highly conserved transmembrane glycoprotein preferentially expressed in the brain. P86L) in CALHM1 could modify the age-at-onset of AD [17,21,22,23], albeit this was not observed in all association studies [24,25]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
