Contribution of ribosome specialization to the pathophysiology of muscular dystrophy

项目摘要/摘要 横纹肌组织含有最高的线粒体含量和已知最大的蛋白质， 这对翻译机器提出了独特的挑战。肌肉组织特异性地表达 一种类似的核糖体蛋白，RLP3L，与普遍存在的RPL3大约80%相似，是 核糖体大亚基的形成所必需的。在肌肉方面，RPL3L替代RPL3 在核糖体中，但这如何改变核糖体功能仍不清楚。此外，这两个人 在肌肉适应、压力和压力条件下，Paralog表现出相反的关系 病理学。在营养不良的肌肉中，RPL3L在核糖体中丢失而有利于RPL3，但对RPL3L的影响 肌肉功能衰退尚不清楚。最近的证据表明，核糖体可以 为了有选择地将某些基因翻译成蛋白质而专门研究。此外，平移控制 已经成为线粒体功能的一层新的调节层，线粒体功能在早期衰退 肌营养不良的病理学，在显性表型之前。综上所述，我假设 营养不良肌肉中RPL3L的丢失会损害核糖体的特化，从而导致失衡 线粒体和肌节蛋白合成之间的关系，加剧营养不良疾病 进步。在肌营养不良症中挽救肌肉特异性核糖体蛋白将提供 核糖体特化在肌肉功能衰退中的作用的第一个证据，并有助于指导 新疗法的设计。拟议的研究还将首次调查 糖皮质激素(治疗营养不良的常用疗法)对肌肉核糖体特化和 翻译选择性。拟议研究的成功完成将揭示新的治疗方法 目标以及慢性衰弱疾病的病理生理学基础的新机制。

Project Summary/Abstract Striated muscle tissue contains the highest mitochondrial content and the largest known proteins, which present unique challenges to the translational machinery. Muscle tissue specifically expresses a paralogous ribosomal protein, RLP3L, that is roughly 80% similar to the ubiquitous RPL3, and is essential to the formation of the large subunit of the ribosome. In muscle, RPL3L substitutes for RPL3 in the ribosome, but how this alters ribosome function remains unknown. Furthermore, these two paralogs demonstrate an inverse relationship under conditions of muscle adaptation, stress, and pathology. In dystrophic muscle, RPL3L is lost in favor of RPL3 in the ribosome, but the effects on muscle functional decline are not understood. Recent evidence suggests that ribosomes can specialize in order to selectively translate certain genes into proteins. Additionally, translation control has emerged as a novel layer of regulation for mitochondrial function, which declines early in the pathology of muscular dystrophy, prior to an overt phenotype. Taken together, I hypothesize that the loss of RPL3L in dystrophic muscle impairs ribosome specialization, thus contributing to an imbalance between mitochondrial and sarcomeric protein synthesis, exacerbating dystrophic disease progression. Rescue of the muscle specific ribosomal protein in muscular dystrophy will provide the first evidence for a role of ribosome specialization in muscle functional decline, and help guide the design of new therapeutics. The proposed studies will also, for the first time, investigate the impact of glucocorticoids (a common therapy for dystrophy) on muscle ribosome specialization and translational selectivity. Successful completion of the proposed studies will reveal new therapeutic targets as well novel mechanisms underlying the pathophysiology of chronic debilitating diseases.