Using LIS1 missense mutations to probe dynein regulatory mechanisms

摘要：越来越明显的是，与不同神经系统疾病相关的基因是相同的 跨越障碍，汇聚在共同的功能通路上。例如，控制 微管运动胞浆动力蛋白1(以下简称动力蛋白)在多个 从皮质畸形到肌萎缩侧索硬化症和其他退行性疾病的疾病[1]。这个马达是 在发育和成熟的神经系统中，广泛的细胞过程是必不可少的[2]。 我们的研究小组对动力蛋白调节蛋白Lis1很感兴趣。作为一个至关重要的动力蛋白调节器，这令人惊讶 PAFAH1B1突变在其他神经系统疾病中尚未发现。我们目前正在 研究一名患有自闭症谱系障碍(ASD)的男孩的新的Lis1错义突变(K351R)， 支持一些Lis1突变可以导致不那么严重的疾病的可能性。大多数，如果不是全部的话，LIS1 其作用与动力蛋白的调节有关。大约20个编码Lis1相互作用或动力蛋白调节的基因 具有潜在的自闭症谱系障碍(ASD)相关突变的蛋白质，因此 动力蛋白的调节可能是ASD的易感因素。还有其他错义突变可能导致 几个在线数据库中的部分功能蛋白质。在这个R21探索性项目中，我们将测试 假设单个Lis1错义突变会破坏特定的Lis1相互作用，从而 辨证调控动力蛋白，影响病情严重程度。我们将确定每个突变是如何 影响关键的LIS1相互作用，以及它们如何影响LIS1的S调节动力蛋白的能力。 这项研究将首次系统地剖析Lis1错义突变对不同人群的影响 蛋白质结构域对动力蛋白功能的影响，以及动力蛋白功能变化与疾病的关系 严肃性。由于神经元对Lis1表达的减少特别敏感，它们可能是负面的 甚至受到Lis1微小变化的影响，这些变化微妙地改变了动力蛋白的功能。因为LIS1在这两个方面都很关键 对于发育中的和成人神经系统，我们的研究可以提供一个跳板来理解 动力蛋白在包括ASD和较晚发病在内的广泛神经疾病中的去调节作用 阿尔茨海默病和肌萎缩侧索硬化症等疾病。

SUMMARY: It is becoming clear that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. For example, pathways that control the microtubule motor cytoplasmic dynein 1 (hereafter referred to as “dynein”) are perturbed in multiple disorders from cortical malformations to ALS and other degenerative diseases [1]. This motor is indispensable for a wide range of cellular processes in the developing and mature nervous system [2]. Our group is interested in the dynein regulatory protein, LIS1. As a vital dynein regulator, it is surprising that PAFAH1B1 mutations have not been found in other neurological diseases. We are currently studying a novel LIS1 missense mutation (K351R) in a boy with Autism Spectrum Disorder (ASD), supporting the possibility that some LIS1 mutations can lead to less severe disease. Most, if not all, LIS1 roles are related to dynein regulation. Around 20 genes encoding LIS1-interacting or dynein regulatory proteins that have potential autism spectrum disorder (ASD)-linked mutations, so perturbations in dynein regulation could predispose to ASD. There are other missense mutations that could lead to partially functional proteins in several online databases. In this R21 exploratory project we will test the hypothesis that individual LIS1 missense mutations will disrupt specific LIS1 interactions, thereby differentially regulating dynein and impacting disease severity. We will determine how each mutation impacts critical LIS1 interactions, and how they impact LIS1’s ability to regulate dynein. This study will be the first to systematically dissect the impact of LIS1 missense mutations in different domains of the protein on dynein function, and to correlate changes in dynein function with disease severity. As neurons are uniquely sensitive to reduced LIS1 expression they might be negatively impacted even by small changes in LIS1 that subtly alter dynein function. Because LIS1 is critical in both the developing and adult nervous system, our studies could provide a springboard for understanding dynein deregulation across a wide range of neurological disorders, including ASD and later onset disorders such as Alzheimer’s Disease and Amyotrophic Lateral Sclerosis.