Molecular Pathophysiology of Familial Cortical Myoclonus

肌阵挛被定义为突然而短暂的肌肉收缩。肌阵挛会导致严重虚弱的不自主运动。它与许多神经疾病有关，但原因尚不清楚。我们最近发现了一个有11名成员患有肌阵挛的大家庭。这个家族性疾病在临床上不同于文献中描述的任何其他疾病，我们称之为“家族性皮质肌阵挛”(FCM)。FCM是遗传的，所以我们使用了一些互补的遗传方法来鉴定NOL3基因的突变。NOL3蛋白是一种称为细胞凋亡的有组织细胞死亡过程的重要抑制因子，特别是在应对脑缺血(中风)和心肌缺血(心肌梗死)时。这项工作的目的是了解NOL3突变是如何导致FCM的。由于突变位于NOL3蛋白的一个基序中，使NOL3能够与其他蛋白质结合，我们假设NOL3突变改变了NOL3蛋白与蛋白质的结合。在目标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的能力的影响。由于NOL3通常抑制细胞凋亡，我们还将研究NOL3突变对细胞凋亡的影响。NOL3很可能与其他蛋白质结合，在目标2中，我们将利用质谱学来鉴定正常和突变的NOL3蛋白的新结合伙伴。最后，在目标3中，我们将利用一个缺失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。总体而言，这项工作将有助于阐明NOL3突变导致FCM的分子机制。此外，这项工作将确定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所证明的那样，这些发现可能更广泛地适用于更常见的疾病，如癫痫。

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.