Role of impaired protein degradation in photoreceptor degeneration

描述（由申请人提供）：本研究项目的长期目标是了解视网膜变性的分子和细胞机制，并寻求缓解或减缓疾病进展的潜在治疗方法。在本研究中，我们拟探讨以下假设：在视网膜色素变性及相关疾病中，导致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靶向蛋白的能力不足，这些蛋白是由于潜在病理而出现的。我们的初步数据表明，在四种不同的小鼠模型中，在光感受器变性的早期阶段观察到蛋白酶体功能不全，在某些情况下，这种损伤在最早的形态学异常被识别之前就变得突出。目的1将致力于两个互补的动物模型，转导，变性棒的蛋白酶体功能不全的详细机制表征

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.