Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation
Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation
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DOI：
10.1016/s0092-8674(00)80356-6
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发表时间：
1997-09-05
期刊：
影响因子：
64.5
通讯作者：
Potter, H
中科院分区：
文献类型：
--
作者：
Li, JH;Xu, M;Potter, H
早老素1和早老素2这两个相关基因的突变是大多数早发性家族性阿尔茨海默病的原因。尽管结构特征表明早老素是膜蛋白，但其功能尚不清楚(S)。我们已经将早老素定位于核膜、相关的间期动点和中心体--所有参与细胞周期调节和有丝分裂的亚细胞结构。早老素与动粒在内核膜核质表面的共存，结合其他结果，提示它们可能作为动粒结合蛋白/受体在染色体组织和分离中发挥作用。我们讨论了家族性阿尔茨海默病的致病途径，其中早老素功能缺陷导致有丝分裂过程中的染色体错误分离，导致细胞凋亡和/或21三体嵌合体。
Mutations in two related genes, presenilin 1 and 2, account for most early-onset familial Alzheimer's disease. Although structural features indicate that the presenilins are membrane proteins, their function(s) is unknown. We have localized the presenilins to the nuclear membrane, its associated interphase kinetochores, and the centrosomes-all subcellular structures involved in cell cycle regulation and mitosis. The colocalization of the presenilins with kinetochores on the nucleoplasmic surface of the inner nuclear membrane, together with other results, suggests that they may play a role in chromosome organization and segregation, perhaps as kinetochore binding proteins/receptors. We discuss a pathogenic pathway for familial Alzheimer's disease in which defective presenilin function causes chromosome missegregation during mitosis, resulting in apoptosis and/or trisomy 21 mosaicism.