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.
Myoclonus can be a symptom of almost any neurologic illness, and can be severely debilitating. Our research aims to elucidate the biological mechanism that causes a rare familial form of myoclonus. Our hope is that, as has proved the case for many other rare diseases, understanding this rare form of myoclonus will also provide insight into more common forms of myoclonus and perhaps other related diseases such as epilepsy.
|Russell, Jonathan F; Fu, Ying-Hui; Ptá?ek, Louis J (2013) Episodic neurologic disorders: syndromes, genes, and mechanisms. Annu Rev Neurosci 36:25-50|
|Russell, Jonathan F; Steckley, Jamie L; Coppola, Giovanni et al. (2012) Familial cortical myoclonus with a mutation in NOL3. Ann Neurol 72:175-83|