Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.
PLoS One. 2013 Sep 17;8(9):e74203. doi: 10.1371/journal.pone.0074203. eCollection 2013.
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 Ca(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.
大脑中的钙信号对于学习和记忆过程至关重要，有证据表明其功能障碍与阿尔茨海默病（AD）的病理途径有关。最近，AD 的钙假说得到了支持，因为发现了非选择性 Ca(2+)-可渗透通道 CALHM1。CALHM1 中的一个遗传多态性（p. P86L）降低了质膜 Ca(2+)通透性，与 AD 的发病年龄较早有关。为了研究 CALHM1 变体在早发性 AD（EOAD）中的作用，我们在三个独立的系列中对所有 CALHM1 编码区进行了测序，这些系列包括 284 名 EOAD 患者和 326 名对照。在患者中发现了两个错义突变（p.G330D 和 p.R154H）和一个对照个体中的一个（p.A213T）。钙成像分析表明，虽然在对照中发现的突变（p.A213T）表现为野生型 CALHM1（CALHM1-WT），但完全消除 Ca(2+)内流与在 EOAD 患者中发现的突变相关（p.G330D 和 p.R154H）。值得注意的是，先前报道的 p. P86L 突变与 CALHM1-WT 和 p.G330D 和 p.R154H 突变之间的中间 Ca(2+)内流相关。由于野生型和突变型 CALHM1 的表达均不影响淀粉样 β-肽（Aβ）的产生或 Aβ介导的细胞毒性，我们得出结论，CALHM1 中的罕见遗传变异导致 Ca(2+)失调，并且可能通过与经典 Aβ级联途径无关的机制导致 EOAD 的风险增加。
