Photoreceptor cell degeneration in D. melanogaster

描述（由申请人提供）：在视觉系统中，光的光子激活视紫红质启动称为光转导级联的事件链。通过调节蛋白抑制蛋白与视紫红质的结合实现级联在一个水平上的失活。视紫红质和arrestin之间通常短暂的相互作用在某些遗传背景下是稳定的，其中arrestin保持非磷酸化形式。视紫红质和抑制蛋白之间的这些稳定复合物的积累是感光细胞凋亡和视网膜变性的直接介质。光感受器细胞变性的第一步是视紫红质/抑制蛋白复合物通过受体介导的内吞作用内化到细胞体中。视紫红质在感光细胞质内以不溶性聚集体的形式积累。这定义了一个新的凋亡信号通路，是负责视网膜变性的果蝇突变体的数量。有趣的是，在几种不同形式的常染色体显性视网膜色素变性中，已经观察到视紫红质和抑制蛋白之间的稳定复合物。此外，许多神经元退行性疾病的特征在于蛋白质复合物的细胞内积累，这表明这可能是用于各种疾病的常见凋亡机制。 为了进一步描述这种新的凋亡途径，将采取三种实验方法。1）。我们将确定是否arrestin和AP 2异源四聚体之间的相互作用是必不可少的视紫红质内吞作用。2）。我们将研究视紫红质和抑制蛋白的内体运输在细胞死亡激活中的作用。3）。将进行遗传筛选以分离参与这种新的凋亡信号通路的基因产物。参与耦合视紫红质/抑制蛋白复合物的形成与细胞死亡机制的基因产物将被确定和表征。

DESCRIPTION (provided by applicant): In the visual system, the activation of rhodopsin by a photon of light initiates a chain of events referred to as the phototransduction cascade. The inactivation of the cascade at one level is achieved by the binding of the regulatory protein arrestin to rhodopsin. The normally transient interaction between rhodopsin and arrestin is stabilized in certain genetic backgrounds where arrestin remains in the unphosphorylated form. The accumulation of these stable complexes between rhodopsin and arrestin are direct mediators of photoreceptor cell apoptosis and retinal degeneration. The initial step in photoreceptor cell degeneration is the internalization of the rhodopsin/arrestin complexes into the cell body via receptor-mediated endocytosis. The rhodopsin accumulates in insoluble aggregates within the photoreceptor cytoplasm. This defines a novel apoptotic signaling pathway that is responsible for retinal degeneration in a number of Drosophila mutants. Interestingly, in several different forms of autosomal dominant retinitis pigmentosa stable complexes between rhodopsin and arrestin have been observed. Moreover, many neuronal degenerative disorders are characterized by the intracellular accumulation of protein complexes, suggesting that this may be a common apoptotic mechanism that is used in a wide variety of diseases. In an effort to further characterize this novel apoptotic pathway three experimental approaches will be undertaken. 1). We will determine if an interaction between arrestin and the AP2 heterotetramer is essential for rhodopsin endocytosis. 2). We will examine the role of endosomal trafficking of rhodopsin and arrestin in the activation of cell death. 3). A genetic screen will be conducted to isolate gene products involved in this novel apoptotic signaling pathway. Gene products involved in coupling rhodopsin/arrestin complex formation with the cell death machinery will be identified and characterized.