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Molecular Pathophysiology of Familial Cortical Myoclonus

家族性皮质肌阵挛的分子病理生理学

基本信息

批准号：
8253263
负责人：
Jonathan Foster Russell
金额：
$ 3.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8253263
关键词：
16q21 Apoptosis Apoptotic Behavioral Binding Biological Brain Brain Ischemia Brain region Cardiac Cell Death Cell Line Chromosomes Co-Immunoprecipitations Code Computer Simulation Databases Dideoxy Chain Termination DNA Sequencing Disease Electrostatics Epilepsy Exhibits Family Functional disorder Genes Genetic Goals Heterodimerization Human Immunohistochemistry Inherited Involuntary Movements Ischemia Knock-out Knockout Mice Link Literature Mass Spectrum Analysis Measures Methods Microsatellite Repeats Modeling Molecular Movement Disorders Mus Muscle Contraction Mutant Strains Mice Mutation Myocardial Infarction Myoclonus Neurologic Neurons Nucleolar Proteins Patients Phenotype Process Protein Binding Proteins Rare Diseases Repression Research Role Signal Pathway Single Nucleotide Polymorphism Map Stroke Surface Symptoms Time Transcript Variant Work cell type gain of function genetic linkage analysis inhibitor/antagonist insight loss of function member mutant nervous system disorder neuronal excitability novel pro-apoptotic protein protein protein interaction response stable cell line tandem mass spectrometry

项目摘要

Myoclonus is defined as sudden and brief muscle contractions. Myoclonus causes involuntary movements that can be severely debilitating. It is associated with many neurologic disorders, but the cause is not known. We recently identified a large family with 11 members suffering from myoclonus. This family's disorder is clinically distinct from any other disorder described in the literature; we have termed it "Familial Cortical Myoclonus" (FCM). FCM is inherited, so we used a number of complementary genetic approaches to identify the mutation in the gene NOL3. NOL3 protein is an important inhibitor of the process of organized cell death called apoptosis, particularly in response to brain ischemia (stroke) and cardiac ischemia (myocardial infarction). The objective of this work is to understand how the mutation in NOL3 causes FCM. Since the mutation resides in a motif of the NOL3 protein that enables NOL3 to bind to other proteins, we hypothesize that the NOL3 mutation alters NOL3 protein-protein binding. In Aim 1, we will use cell lines to investigate the effect of the mutation on the ability of NOL3 to bind its known binding partners. Since NOL3 normally inhibits apoptosis, we will also investigate the effect of the NOL3 mutation on apoptosis. It is likely that NOL3 binds other proteins, and in Aim 2, we will utilize mass spectrometry to identify novel binding partners of the normal and mutant NOL3 protein. Finally, in Aim 3 we will utilize a mutant mouse lacking the NOL3 gene to investigate the role of normal and mutant NOL3 in neuronal excitability. Overall, this work will help elucidate the molecular mechanism by which the mutation in NOL3 causes FCM. In addition, this work will identify novel binding partners of NOL3 and will link NOL3 to neuronal excitability. As has proved the case for many other rare disorders, these discoveries may be more broadly applicable to much more common disorders such as epilepsy.

肌阵挛被定义为突然和短暂的肌肉收缩。肌阵挛会引起不自主的运动，严重削弱身体。它与许多神经系统疾病有关，但病因尚不清楚。我们最近发现了一个大家庭，有11名成员患有肌阵挛。这个家族的疾病在临床上与文献中描述的任何其他疾病都不同；我们称之为“家族性皮质肌阵挛”（FCM）。FCM是遗传性的，因此我们使用了许多互补的遗传方法来确定基因NOL3的突变。NOL3蛋白是有组织细胞死亡（称为凋亡）过程的重要抑制剂，特别是在脑缺血（中风）和心脏缺血（心肌梗死）时。这项工作的目的是了解NOL3突变如何导致FCM。由于该突变位于NOL3蛋白的一个基序中，该基序使NOL3能够与其他蛋白结合，因此我们假设NOL3突变改变了NOL3蛋白的蛋白结合。在Aim 1中，我们将使用细胞系来研究突变对NOL3结合其已知结合伙伴能力的影响。由于NOL3通常抑制细胞凋亡，我们也将研究NOL3突变对细胞凋亡的影响。NOL3很可能与其他蛋白结合，在Aim 2中，我们将利用质谱法鉴定正常和突变NOL3蛋白的新结合伙伴。最后，在Aim 3中，我们将利用缺乏NOL3基因的突变小鼠来研究正常和突变的NOL3在神经元兴奋性中的作用。总的来说，这项工作将有助于阐明NOL3突变导致FCM的分子机制。此外，本工作将确定NOL3的新结合伙伴，并将NOL3与神经元兴奋性联系起来。正如许多其他罕见疾病的情况所证明的那样，这些发现可能更广泛地适用于癫痫等更常见的疾病。