Role of stress responses in regulating photoreceptor structural plasticity

摘要 神经系统必须适应环境的快速和缓慢变化。一个经典的例子是 能适应几个数量级的光线级别变化的视觉系统 在短短几秒钟内。适应也是在更长的时间尺度上观察到的，例如 光照期间的季节变化。在果蝇中，转换到延长的光期触发了 感光细胞对光敏感的细胞器横纹肌的尺寸减小，以及 下调了它们的突触活动区。我们最近发现，对此的监管 结构的可塑性取决于未折叠蛋白反应(UPR)。在仅仅一晚之后 持续的光照下，UPR的Irei和Perk臂都被激活。干扰 随着UPR的正常调节，导致视神经传递的丧失和严重 横纹肌的结构退化，容纳关键元素的微绒毛阵列 光传导级联反应。这一表型在Fic和Bip突变体中观察到 干扰普遍定期审议的主要监管者--国际和平研究所的活动。筛选 在这个途径的其他元件中，我们发现了一种非传统的类似激酶的蛋白，称为 通宵达旦，作为候选人。它的序列预测该蛋白可能是一种作用于 分泌途径。初步数据表明，类似于Fic和Bip突变体，延长了 光周期导致整夜突变体失去视觉神经传递和结构完整性 横纹肌的。这项提议旨在描述光感受器的调控机制。 结构可塑性和通宵在这一过程中的具体作用。具体地说，我们将测试 如何调控两条关键的应激途径，即未折叠的蛋白质反应和自噬， 有助于结构可塑性和通宵蛋白的修饰机制 这两条路都是。这些实验的完成将显著提高我们的 对光感受器结构可塑性驱动和维持机制的理解 长期适应过程中的视力。

Abstract Neuronal systems must adapt to fast and slow changes in the environment. A classic example is the visual system which can adjust to changes in several orders of magnitude in light levels within just seconds. Adaptation has also been observed on a much longer time scale, such as seasonal changes in the light period. In Drosophila, shifts to an extended light period trigger a reduction in the size of rhabdomeres, the light-sensitive organelle of photoreceptors, and a down regulation of their synaptic active zones. We recently discovered that regulation of this structural plasticity depends on the unfolded protein response (UPR). After just one night with continued light exposure, both the IreI and the PERK arm of the UPR are activated. Interference with the normal regulation of the UPR results in the loss of visual neurotransmission and severe structural deterioration of rhabdomeres, the microvillar arrays that house the key elements of the phototransduction cascade. This phenotype was observed for fic and BiP mutants that interfere with the regulation of the activity of BiP, a major regulator of the UPR. Screening for additional elements of this pathway, we identified an unconventional kinase-like protein, called Allnighter, as a candidate. Its sequence predict that this protein may be a kinase acting in the secretory pathway. Preliminary data indicate that, similar to fic and BiP mutants, an extended light period causes allnighter mutants to lose visual neurotransmission and structural integrity of rhabdomeres. This proposal aims to characterize the mechanisms regulating photoreceptor structural plasticity and the specific role of Allnighter in this process. Specifically, we will test how regulation of two key stress pathways, the unfolded proteins response and autophagy, contributes to structural plasticity and the mechanisms by which the Allnighter protein modifies both of these pathways. Completion of these experiments will significantly enhance our understanding of the mechanism that drive structural plasticity of photoreceptors and maintain visual acuity during long-term adaptation.