权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Using LIS1 missense mutations to probe dynein regulatory mechanisms

利用 LIS1 错义突变探测动力蛋白调节机制

基本信息

批准号：
10544530
负责人：
DEANNA S SMITH
金额：
$ 21.91万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544530
关键词：
ASD patient Address Adult Alzheimer&apos s Disease Amino Acid Substitution Amyotrophic Lateral Sclerosis Axon Axonal Transport Benign Binding Biological Assay Brain Diseases COS-7 Cell Categories Cell physiology Cessation of life Childhood ClinVar Complex Cortical Malformation Cytoplasm Data Set Databases Degenerative Disorder Development Developmental Brain Malformation Disease Dynein ATPase Genes Impaired cognition Individual LIS1 protein Late-Onset Disorder Link Measures Microtubules Mild Dysplasia Missense Mutation Motor Motor Activity Mutation Nervous System Neurologic Neurons Nomenclature Organelles Pathway interactions Patients Phenotype Proteins Regulation Reporting Role Seizures Severity of illness Tertiary Protein Structure Testing autism spectrum disorder autosomal dominant mutation boys dominant genetic mutation genetic regulatory protein interest lissencephaly migration motor impairment mutant nervous system disorder novel protein function

项目摘要

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.

摘要：越来越清楚的是，与不同神经系统疾病相关的基因是共享的跨越疾病并集中在共同的功能途径上。例如，控制通路微管运动细胞质动力蛋白 1（以下简称“动力蛋白”）受到多种干扰从皮质畸形到 ALS 和其他退行性疾病等疾病[1]。该电机是对于发育和成熟神经系统中的广泛细胞过程不可或缺[2]。我们小组对动力蛋白调节蛋白 LIS1 感兴趣。作为重要的动力蛋白调节剂，令人惊讶 PAFAH1B1突变尚未在其他神经系统疾病中发现。我们目前研究一名患有自闭症谱系障碍 (ASD) 男孩的新型 LIS1 错义突变 (K351R)，支持某些 LIS1 突变可能导致不太严重的疾病的可能性。大多数（如果不是全部）LIS1 作用与动力蛋白调节有关。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自闭症谱系障碍（ASD）相关突变的蛋白质，因此扰动动力蛋白调节可能导致自闭症谱系障碍（ASD）。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，从而差异调节动力蛋白并影响疾病的严重程度。我们将确定每个突变如何影响关键的 LIS1 相互作用，以及它们如何影响 LIS1 调节动力蛋白的能力。这项研究将是第一个系统剖析 LIS1 错义突变在不同疾病中的影响的研究。蛋白质结构域对动力蛋白功能的影响，并将动力蛋白功能的变化与疾病相关联严重程度。由于神经元对 LIS1 表达减少特别敏感，因此它们可能会产生负面影响即使 LIS1 的微小变化也会影响动力蛋白的功能。因为 LIS1 在这两个方面都至关重要发育中的成人神经系统，我们的研究可以为理解提供一个跳板动力蛋白失调导致多种神经系统疾病，包括 ASD 和晚发型阿尔茨海默病和肌萎缩侧索硬化症等疾病。