Myoclonus-dystonia (M-D) is an inherited movement disorder characterized predominantly by involuntary jerking of the upper body (myoclonus) and sustained contraction of agonist and antagonist muscles that result in painful, twisted postures (dystonia). Motor symptoms onset in childhood or adolescence and cause varying degrees of pain, disability, and psychosocial distress. M-D is caused by loss-of-function mutations in the gene SGCE, which encodes the protein epsilon sarcoglycan (?-sg), but the pathophysiology of the disorder remains poorly understood. There is currently is no cure or effective treatment for M-D. A striking characteristic of this disorder is that motor symptoms improve with alcohol consumption. While alcohol may be inappropriate for therapy, understanding how it acts to relieve symptoms would offer insights into the pathophysiology of M-D and provide potential therapeutic targets. The cerebellum is exquisitely sensitive to alcohol and has recently been implicated in the pathophysiology of some dystonias. Preliminary data obtained in this lab also implicate cerebellum in M-D. The purpose of the proposed study is to test the hypothesis that aberrant activity of the cerebellum causes myoclonus and dystonia in M-D and that by acting on targets in the cerebellum, alcohol normalizes cerebellar activity to relieve motor symptoms. Preliminary data suggests that acute knockdown of mouse sgce in the cerebellum by short hairpin RNA (shRNA) leads to alcohol-responsive myoclonus and dystonia that is correlated with aberrant cerebellar activity.
The first aim i s to expand on these data and identify the effect of sgce knockdown on particular cell types in the cerebellum. The effects of sgce knockdown on Purkinje cells and DCN neurons in vivo will be characterized by single-unit recordings in awake, head-restrained mice, while slice electrophysiology will be used to dissect the mechanism underlying these effects. Completion of this aim will further illustrate the role of cerebellar dysfunction in movement disorders and identify particular cell types that contribute to the development of myoclonus and dystonia in M-D.
The second aim i s to elucidate the mechanism by which alcohol improves symptoms in the sgce shRNA knockdown model. This will be the first study to examine the mechanism underlying the therapeutic effect of alcohol on motor symptoms in M-D. In vivo electrophysiology will be used to test the hypothesis that ethanol improves dystonic symptoms in sgce shRNA-injected mice by restoring the normal firing pattern of Purkinje cells and DCN neurons. Pharmacological manipulation of proposed targets of ethanol will then enable identification of potential receptors or proteins with which ethanol interacts to relieve symptoms in M-D. Completion of this aim would provide potential targets for the treatment of M-D and shed light on some of the mechanisms by which alcohol acts in the brain.

Public Health Relevance

Myoclonus-dystonia is a poorly understood movement disorder that causes physical disability and social anxiety. Current treatment options provide little to no improvement in symptoms. The proposed research will (1) shed light on the underlying neurological cause of myoclonus and dystonia in M-D and (2) provide biological targets for the development of effective, non-invasive treatment options for M-D that address the underlying neurological dysfunction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F02A-J (20))
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Sieber, Beth-Anne
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Albert Einstein College of Medicine
Schools of Medicine
United States
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