Role of impaired protein degradation in photoreceptor degeneration

描述(申请人提供)：这项研究计划的长期目标是了解视网膜变性的分子和细胞机制，并寻找潜在的治疗方法来缓解或减缓疾病的进展。在这一应用中，我们建议探索一种假设，即导致视网膜色素变性和相关疾病中光感受器细胞死亡的一个主要应激因素是蛋白酶体降解大量错误折叠或错误定位的蛋白质的能力不足，这些蛋白质是潜在的病理结果。我们的初步数据表明，在四种不同的小鼠模型中，在光感受器退化的早期阶段观察到蛋白酶体功能不足，在某些情况下，这种损害在最早的形态异常被识别之前就变得突出。目标1将致力于在两个互补的动物模型，转导蛋白，蛋白酶体不足的退化杆的详细的机制描述 γ-亚基敲除和P23H小鼠。最重要的是，我们将讨论受影响的光感受器是否遭受蛋白酶体超载，即其蛋白酶体处理异常高负荷的错误折叠蛋白质的能力不足，或者潜在的病理通过抑制蛋白酶体的活性或改变其亚单位组成来直接影响蛋白酶体。Aim 2将探索 蛋白酶体功能不全在不同形式的视网膜变性中的流行率。我们将测试是否可以在光转导级联中遭受异常信号的视杆细胞中检测到它，并阐明它是否发生在遭受突变的小鼠身上，这些突变对视锥细胞的影响比视杆细胞更大。目的3将评估蛋白酶体是否可以作为治疗视网膜退行性疾病的靶点。我们将探索是否可以通过基因治疗或药物治疗来延缓或预防病理的发生，这些治疗旨在增加受影响的光感受器中的蛋白酶体活性。

DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the molecular and cellular mechanisms underlying retinal degeneration and to seek potential therapeutic approaches alleviating or slowing disease progression. In this application, we propose to explore the hypothesis that a major stress factor contributing to photoreceptor cell death in retinitis pigmentosa and related diseases is insufficient ability of proteasomes to degrade large amounts of misfolded or mistargeted proteins that appear as a result of the underlying pathology. Our preliminary data indicate that proteasomal insufficiency is observed at early stages of photoreceptor degeneration in four different mouse models and, in some cases, this impairment becomes prominent before the earliest morphological abnormalities could be identified. Aim 1 will be devoted to a detailed mechanistic characterization of proteasomal insufficiency in degenerating rods of two complementary animal models, transducin γ-subunit knockout and P23H mouse. Most importantly, we will address whether affected photoreceptors suffer from proteasomal overload, i.e. insufficient capacity of their proteasomes to process abnormally high loads of misfolded proteins, or the underlying pathology affects proteasomes directly by inhibiting their activity or altering their subunit composition. Aim 2 will explore the prevalence of proteasomal insufficiency across different forms of retinal degeneration. We will test whether it could be detected in rods suffering from aberrant signaling in the phototransduction cascade and elucidate whether it takes place in mice suffering from mutations which affect cones more significantly than rods. Aim 3 will evaluate whether proteasomes could serve as a therapeutic target in treating retinal degenerative diseases. We will explore whether the onset of pathology can be slowed or prevented by gene therapy or pharmacological treatments designed to increase proteasomal activity in affected photoreceptors.