Photoreceptor cell degeneration in D. melanogaster

黑腹果蝇感光细胞变性

• 批准号: 6984765
• 负责人: PATRICK J. DOLPH
• 金额: $ 28.54万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984765
• 关键词: Drosophilidae; apoptosis; arrestins; genetic screening; laboratory rabbit; protein binding; protein protein interaction; receptor mediated endocytosis; retina degeneration; rhodopsin; visual photoreceptor; visual phototransduction; western blottings

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.

描述（由申请人提供）：在视觉系统中，一个光子激活视紫红质启动一系列事件，称为光导级联。级联在一个水平上的失活是通过调节蛋白阻滞蛋白与视紫红质的结合来实现的。视紫红质和抑制蛋白之间通常短暂的相互作用在某些遗传背景下是稳定的，其中抑制蛋白保持在未磷酸化的形式。这些稳定复合物在视紫红质和阻滞蛋白之间的积累是光感受器细胞凋亡和视网膜变性的直接介质。光感受器细胞退化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在化到细胞体中。视紫红质以不溶性聚集体在光感受器细胞质内积累。这定义了一种新的凋亡信号通路，该通路负责许多果蝇突变体的视网膜变性。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是细胞内蛋白质复合物的积累，这表明这可能是一种常见的凋亡机制，用于各种疾病。