Dynamic RNA-protein assemblies and neurological disease

RNA代谢紊乱已成为几种相关神经系统疾病的重要因素，包括肌萎缩性侧索硬化症（ALS）、额颞叶痴呆（FTD）和包涵体肌病（IBM）。这些退行性疾病的家族性和散发性形式的典型病理特征是由rna结合蛋白（rbp）的纤维沉积物组成的细胞质包涵体。此外，rbp或其他调节RNA代谢的蛋白质的突变经常导致这些疾病的家族性形式。在过去的7年里，我的实验室一直处于阐明这些疾病的分子基础的前沿，包括识别新的疾病基因，阐明这些和其他疾病相关基因的正常功能，以及确定疾病突变的后果。基于这些研究，我们提出了一种假设，即各种RNA-蛋白组合（包括细胞质RNA颗粒）的组装、拆卸和功能紊乱是上述神经系统疾病的发病机制的基础。我们已经制定了一个全面的研究计划，在接下来的8年里，将研究RNA颗粒组装的分子基础，详细阐明RNA颗粒动力学是如何被调节的，确定RNA颗粒在基因表达的时空控制中的作用，最重要的是阐明RNA颗粒动力学缺陷导致神经系统疾病的机制。

Disturbances in RNA metabolism have emerged as an important contributor to several related neurological diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion body myopathy (IBM). The familial and sporadic forms of these degenerative diseases are typically characterized pathologically by cytoplasmic inclusions composed of fibrillar deposits of RNA-binding proteins (RBPs). Moreover, mutations in RBPs or other proteins that regulate RNA metabolism frequently cause the familial forms of these diseases. Over the past 7 years my lab has been at the forefront of illuminating the molecular basis for these diseases, including identifying new diseases genes, elucidating the normal function of these and other disease-related genes, and determining the consequences of disease mutations. Based on these studies we have advanced the hypothesis that disturbance in the assembly, disassembly and function of diverse RNA-protein assemblies, including cytoplasmic RNA granules, underlies the pathogenesis of the aforementioned neurological diseases. We have developed a comprehensive research program that, over the next 8 years, will investigate the molecular bases of RNA granule assembly, elucidate in detail how RNA granule dynamics are regulated, determine the role of RNA granules in spatial and temporal control of gene expression, and most importantly elucidate the mechanism whereby defects in RNA granule dynamics contribute to neurological diseases.