Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
PLoS One. 2009 Sep 4;4(9):e6904. doi: 10.1371/journal.pone.0006904.
Much of our current understanding about neurodegenerative diseases can be attributed to the study of inherited forms of these disorders. For example, mutations in the presenilin 1 and 2 genes have been linked to early onset familial forms of Alzheimer's disease (FAD). Using the Drosophila central nervous system as a model we have investigated the role of presenilin in one of the earliest cellular defects associated with Alzheimer's disease, intracellular calcium deregulation. We show that expression of either wild type or FAD-mutant presenilin in Drosophila CNS neurons has no impact on resting calcium levels but does give rise to deficits in intracellular calcium stores. Furthermore, we show that a loss-of-function mutation in calmodulin, a key regulator of intracellular calcium, can suppress presenilin-induced deficits in calcium stores. Our data support a model whereby presenilin plays a role in regulating intracellular calcium stores and demonstrate that Drosophila can be used to study the link between presenilin and calcium deregulation.
我们目前对神经退行性疾病的许多了解都可以归因于对这些疾病遗传形式的研究。例如，早发性家族性阿尔茨海默病（FAD）中存在早老素 1 和 2 基因突变。我们使用果蝇中枢神经系统作为模型，研究了早老素在与阿尔茨海默病相关的最早的细胞缺陷之一——细胞内钙失调中的作用。我们发现，野生型或 FAD 突变型早老素在果蝇中枢神经系统神经元中的表达对静息钙水平没有影响，但确实导致细胞内钙储存缺陷。此外，我们还表明，钙调蛋白（一种细胞内钙的关键调节剂）的功能丧失突变可以抑制早老素诱导的钙储存缺陷。我们的数据支持这样一种模型，即早老素在调节细胞内钙储存中发挥作用，并证明果蝇可用于研究早老素与钙失调之间的联系。
