Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson's disease phenotypes.
Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson's disease phenotypes.
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DOI：
10.1016/j.nbd.2017.04.014
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发表时间：
2017-08
影响因子：
6.1
通讯作者：
Hodge JJL
中科院分区：
文献类型：
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作者：
Julienne H;Buhl E;Leslie DS;Hodge JJL
帕金森氏病(PD)更常见的是与其运动症状和相关的多巴胺(DA)神经元变性有关。然而，越来越清楚的是，帕金森病患者也表现出广泛的非运动症状，包括记忆缺陷和睡眠-觉醒周期中断。这些症状对他们的生活质量有很大影响，通常在运动症状出现之前，但其病因尚不清楚。果蝇已经被成功地用来建立帕金森病的模型，并被广泛用于研究其他环境中相关的非运动行为，但在这种遗传易驯化的生物中模拟帕金森病的非运动症状还很少受到关注。我们检测了果蝇的记忆表现和昼夜节律，果蝇的两个PD基因：PINK1和parkin发生了功能丧失突变。我们发现这两种突变基因都存在学习和记忆异常，以及由时钟神经元的电生理变化支撑的昼夜节律减弱。我们的研究为进一步的工作铺平了道路，这些工作可能有助于我们理解帕金森病这些被忽视的方面的潜在机制，从而确定新的治疗靶点，以专门解决这些非运动问题，甚至可能阻止疾病在其前驱阶段的发展。果蝇PINK1和Parkin功能丧失(LOF)突变体存在记忆缺陷。果蝇PINK1和Parkin LOF突变体削弱了昼夜节律。果蝇PINK1和parkin LOF突变体存在时钟神经元电生理缺陷。果蝇是研究帕金森氏症非运动症状的有力模型。
Parkinson's disease (PD) is more commonly associated with its motor symptoms and the related degeneration of dopamine (DA) neurons. However, it is becoming increasingly clear that PD patients also display a wide range of non-motor symptoms, including memory deficits and disruptions of their sleep-wake cycles. These have a large impact on their quality of life, and often precede the onset of motor symptoms, but their etiology is poorly understood. The fruit fly Drosophila has already been successfully used to model PD, and has been used extensively to study relevant non-motor behaviours in other contexts, but little attention has yet been paid to modelling non-motor symptoms of PD in this genetically tractable organism. We examined memory performance and circadian rhythms in flies with loss-of-function mutations in two PD genes: PINK1 and parkin. We found learning and memory abnormalities in both mutant genotypes, as well as a weakening of circadian rhythms that is underpinned by electrophysiological changes in clock neurons. Our study paves the way for further work that may help us understand the mechanisms underlying these neglected aspects of PD, thus identifying new targets for treatments to address these non-motor problems specifically and perhaps even to halt disease progression in its prodromal phase. Drosophila PINK1 and parkin loss-of-function (LOF) mutants have memory deficits. Drosophila PINK1 and parkin LOF mutants have weakened circadian rhythms. Drosophila PINK1 and parkin LOF mutants have clock neuron electrophysiology defects. Drosophila is a powerful model for studying Parkinson's disease non-motor symptoms.