Lu Yisheng, Lv Yubing, Ye Yihong, Wang Yalin, Hong Yu, Fortini Mark E, Zhong Yi, Xie Zuoping
State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China 100084.
FASEB J. 2007 Aug;21(10):2368-78. doi: 10.1096/fj.06-6380com. Epub 2007 Apr 11.
It has been shown that presenilin is involved in maintaining Ca2+ homeostasis in neurons, including regulating endoplasmic reticulum (ER) Ca2+ storage. From studies of primary cultures and cell lines, however, its role in stress-induced responses is still controversial. In the present study we analyzed the effects of presenilin mutations on membrane currents and synaptic functions in response to stress using an in vivo preparation. We examined voltage-gated K+ and Ca2+ currents at the Drosophila larval neuromuscular junction (NMJ) with voltage-clamp recordings. Our data showed that both currents were generally unaffected by loss-of-function or Alzheimer's disease (AD) -associated presenilin mutations under normal or stress conditions induced by heat shock (HS) or ER stress. In larvae expressing the mutant presenilins, prolonged Ca2+ tail current, reflecting slower deactivation kinetics of Ca2+ channels, was observed 1 day after stress treatments were terminated. It was further demonstrated that the L-type Ca2+ channel was specifically affected under these conditions. Moreover, synaptic plasticity at the NMJ was reduced in larvae expressing the mutant presenilins. At the behavioral level, memory in adult flies was impaired in the presenilin mutants 1 day after HS. The results show that presenilin function is important during the poststress period and its impairment contributes to memory dysfunction observed during adaptation to normal conditions after stress. Our findings suggest a new stress-related mechanism by which presenilin may be implicated in the neuropathology of AD.
已表明早老素参与维持神经元中的Ca2+稳态，包括调节内质网（ER）的Ca2+储存。然而，从原代培养物和细胞系的研究来看，其在应激诱导反应中的作用仍存在争议。在本研究中，我们使用体内实验准备分析了早老素突变对应激反应中膜电流和突触功能的影响。我们通过电压钳记录检查了果蝇幼虫神经肌肉接头（NMJ）处的电压门控K+和Ca2+电流。我们的数据表明，在热休克（HS）或内质网应激诱导的正常或应激条件下，功能丧失或与阿尔茨海默病（AD）相关的早老素突变通常不会影响这两种电流。在表达突变早老素的幼虫中，应激处理终止1天后观察到Ca2+尾电流延长，这反映了Ca2+通道失活动力学减慢。进一步证明在这些条件下L型Ca2+通道受到特异性影响。此外，表达突变早老素的幼虫中NMJ处的突触可塑性降低。在行为水平上，HS后1天，早老素突变体成年果蝇的记忆受损。结果表明，早老素功能在应激后时期很重要，其受损导致应激后适应正常条件期间观察到的记忆功能障碍。我们的发现提示了一种新的与应激相关的机制，早老素可能通过该机制参与AD的神经病理学过程。
