Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis.
Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis.
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早老素作为内质网钙渗漏通道和阿尔茨海默氏病的发病机制。
DOI：
10.1007/s11427-011-4201-y
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Bezprozvanny,Ilya
中科院分区：
文献类型：
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作者：
Supnet,Charlene;Bezprozvanny,Ilya
阿尔茨海默病(AD)是世界上最常见的神经退行性疾病，目前是无法治愈的。有毒的淀粉样β蛋白(Aβ)多肽聚集体在AD脑中的积累被认为引发了与认知能力下降有关的广泛突触丢失和神经退行性变，这一观点是家族性(FAD)和散发性AD病因学的淀粉样假说的基础。导致FAD的基因突变也会导致神经元钙(Ca~(2+))处理的失调，并可能参与AD的发病机制，这一想法被称为AD的“钙假说”。早老素蛋白的突变是FAD病例的主要原因。早老素是γ分泌酶的催化亚单位，参与了Aβ多肽的合成。最近，我们发现早老素是一种低电导、被动的内质网钙离子泄漏通道，不依赖于γ分泌酶的活性。我们进一步发现，早老素中的许多FAD突变导致内质网钙泄漏功能的丧失和内质网钙超载。这些结果为在早产儿突变的FAD细胞中观察到的异常钙信号提供了潜在的解释。本文讨论了我们对早老素的内质网钙离子泄漏通道功能的最新研究工作，以及这些发现对理解AD发病机制的意义。
Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the ‘amyloid hypothesis’ of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca2+) handling and may contribute to AD pathogenesis, an idea termed the ‘calcium hypothesis’ of AD. Mutations in presenilin proteins account for majority of FAD cases. Presenilins function as catalytic subunit of γ-secretase involved in generation of Aβ peptide Recently, we discovered that presenilns function as low-conductance, passive ER Ca2+leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins result in loss of ER Ca2+leak function activity and Ca2+overload in the ER. These results provided potential explanation for abnormal Ca2+signaling observed in FAD cells with mutations in presenilns. Our latest work on studies of ER Ca2+leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.