Kv4 Channels as a Target of Aging and Beta-Amyloid

苏珊，秋田 项目摘要 年龄可能是导致多种神经系统疾病的最重要因素，包括 阿尔茨海默病(AD)。我们的主要假设是，在正常衰老过程中受影响的蛋白质靶标可能 在与年龄相关的疾病情况下尤其容易受到影响。在本方案中，我们将重点放在与电压相关的 K+通道，Kv4作为这样的靶点。多项研究发现，Aβ42诱导Kv4通道下降， 导致下游的认知和运动病理。在这里，我们将检查是否有下降的 具有正常老化的Kv4通道，无论是正常衰老和 β42的积累会导致Kv4的进行性丢失，以及Kv4的丢失是否会导致早期衰老和 缩短的寿命。果蝇提供了将其强大的分子遗传学工具包与 研究衰老/Aβ42积累如何影响神经元信号转导的短暂寿命。我们建议：1)测试 通过检测Kv4信使核糖核酸、蛋白水平和蛋白水平，推测Kv4通道随着年龄的增长而逐渐丧失 局部化，以及电流，2)检验年龄/Aβ42依赖的ROS积累的假设 影响Kv4通道，以及3)测试正常的与年龄相关的运动活动和寿命下降是否得到改善 Kv4的水平在基因上是恢复的，当Kv4缺失时，Kv4的水平会加剧。

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.