Novel Locus Required For Photoreceptor Survival

描述(申请人提供)：导致老年性黄斑变性(AMD)和视网膜色素变性(RP)光感受器细胞死亡的基因缺陷是高度异质性的，现在包括超过132个基因。使用果蝇作为分子遗传模型来解开视网膜退行性疾病(如AMD和RP)中的遗传位点，我们最近发现了一类全新的分子，它们对光感受器活性和细胞功能至关重要。这是一类钠依赖的共转运体或共转运体，它通过跨膜移动小分子来换取钠。果蝇和人类的光感受器都有几个运输系统，如钠/钙(-钾)交换系统(NCKX)和ABC转运蛋白。基于果蝇和人类视觉系统的这些和其他相似之处，我们认为钠依赖的转运蛋白可能是某些遗传形式的人类视网膜变性的关键基因。钠依赖共转运体的突变导致果蝇的光感受器病理和年龄相关的视网膜退化。此外，这些突变还会导致视紫红质分子量的缺陷。我们提出了钠依赖的共转运蛋白和视紫红质之间的联系。在许多情况下，钠依赖的共转运体在保护细胞免受氧化损伤方面至关重要。氧化损伤被认为与AMD和RP以及糖尿病视网膜病变有关。因此，钠依赖转运体可能是某些形式的视网膜变性的重要基因座。揭示新的分子类别开辟了全新的研究领域以及新的治疗策略的开发。我们的数据继续支持这样一个概念，即对果蝇的研究对于揭示人类视网膜退化的基础非常有价值。果蝇提供了对新类别蛋白质的快速洞察，这些蛋白质是光感受器功能和视网膜疾病的有力候选者。这一应用的高度影响和创新之处在于利用果蝇分子遗传学的力量，为视网膜退行性疾病的新基因位点和机制提供必要的见解。这项研究通过果蝇和人类遗传学实验室的合作，提供了果蝇和人类之间的快速翻译。

DESCRIPTION (provided by applicant): Genetic defects that lead to photoreceptor cell death in age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are highly heterogeneous and now include a list of more than 132 genes. Using Drosophila as a molecular genetic model for unraveling genetic loci in retinal degeneration disorders, such as AMD and RP, we have recently identified an entirely new class of molecules that are critical to photoreceptor viability and cell function. This is a class of sodium dependent symporters or co-transporters that move small molecules across membranes in exchange for sodium. Photoreceptors in Drosophila and humans alike possess several transport systems such as the sodium/calcium (-potassium) exchangers (NCKX) and the ABC transporters. Based on these and other similarities between Drosophila and human visual systems, we propose that the sodium dependent transporters may be critical loci in certain genetically inherited forms of human retinal degeneration. Mutations in the sodium dependent co-transporter lead to photoreceptor pathology and age-related retinal degeneration in Drosophila. In addition, these mutations also cause defects in the molecular weight of rhodopsin. We propose a link between the sodium dependent co-transporter and rhodopsin. In many cases, sodium dependent co-transporters are critical in protecting cells against oxidative damage. Oxidative damage is thought to contribute to AMD and RP as well as diabetic retinopathy. Therefore, sodium dependent transporters may be important loci in some forms of retinal degeneration. Unmasking novel classes of molecules opens up whole new areas of research as well as the development of new therapeutic strategies. Our data continue to support the concept that studies in Drosophila are highly valuable for uncovering the basis of retinal degeneration in humans. Drosophila offers quick insight into new classes of proteins that are strong candidates for photoreceptor function and retinal disease. The high impact and innovation in this application is to utilize the power of Drosophila molecular genetics to provide needed insights into novel loci and mechanisms in retinal degeneration disease. This study provides a rapid translation between Drosophila and humans through collaboration between Drosophila and human genetics laboratories.