Kv4 Channels as a Target of Aging and Beta-Amyloid

Tsunoda，Susan 项目摘要 年龄可能是多种神经系统疾病的最重要因素，包括 阿尔茨海默病（AD）。我们的总体假设是，在正常衰老过程中受到影响的蛋白质靶点可能 特别是在与年龄有关的疾病中。在这个建议中，我们专注于电压依赖性 K+通道，Kv 4，作为这样的目标。多项研究发现，Aβ42诱导Kv 4通道下降， 会导致下游的认知和运动疾病在这里，我们将研究是否有下降， Kv 4通道与正常老化，是否活性氧（ROS），无论是与正常老化， Aβ42积累导致Kv 4的这种进行性丧失，以及Kv 4的丧失是否导致早期衰老的迹象， 寿命缩短果蝇提供了一个理想的模型，将其强大的分子遗传工具箱与 研究衰老/Aβ42积累如何影响神经元信号传导。我们建议：1）测试 通过检测Kv 4 mRNA、蛋白质水平和 定位，以及电流，2）以检验年龄/Aβ42依赖性ROS蓄积 影响Kv 4通道，以及3）测试当 Kv 4的水平在基因上得到恢复，并且在Kv 4缺失时加剧。

Tsunoda, Susan Project Summary Age is perhaps the most significant contributing factor to multiple neurological diseases, including Alzheimer’s Disease (AD). Our overarching hypothesis is that protein targets affected during normal aging may be especially affected in age-related disease conditions. In this proposal, we focus on the voltage-dependent K+ channel, Kv4, as such a target. Multiple studies have found that Aβ42 induces a decline in Kv4 channels that contributes to downstream cognitive and motor pathologies. Here, we will examine whether there is a decline in Kv4 channels with normal aging, whether reactive oxygen species (ROS) that arise with both normal aging and Aβ42 accumulation lead to this progressive loss of Kv4, and whether loss of Kv4 leads to signs of early aging and a shortened lifespan. Drosophila offers an ideal model for combining its powerful molecular-genetic toolkit with a short lifespan to study how aging/Aβ42 accumulation affects neuronal signaling. We propose: 1) to test the hypothesis that Kv4 channels are progressively lost with age by examining Kv4 mRNA, protein level and localization, as well as current, 2) to test the hypothesis that the age/Aβ42-dependent accumulation of ROS affects Kv4 channels, and 3) to test if normal age-related decline in motor activity and lifespan are improved when levels of Kv4 are genetically restored, and exacerbated when Kv4 is absent.