Grant: Fellowship - Priority Announcement: Dystonia (SHOPP)

Myoclonus dystonia (MD) is a neurological disorder characterized by rapid muscle contractions (myoclonus) and sustained twisting movements resulting in abnormal postures (dystonia). Symptoms begin in the 1st or 2nd decades of life and are associated with subtle psychiatric symptoms (obsessive-compulsive disorder). MD can range from mild to severe, even in the same family. Most patients have a drastic reduction of myoclonus in response to alcohol ingestion, however, as the alcohol level in their system lowers, their symptoms become worse than before. This temporary and severe rebound affect makes alcoholism a significant problem. Forty percent of MD patients have mutations in the gene e-sarcoglycan (SGCE), which is a member of the sarcoglycan (SG) family. To date, 6 sarcoglycan genes (a,b, e,g,d,and z) have been identified. Mutations in a, b, g and d sarcoglycan are responsible for recessive (both parents must be carriers) limb-girdle muscular dystrophy. The sarcoglycans are members of the dystrophin-dystroglycan complex (DGC) in muscle. Mutations in other members of the complex are also responsible for other forms of muscular dystrophies. Interestingly, SGCE is expressed in more tissues than the other family members. Its expression within the brain explains how a mutation in the gene encoding SGCE causes the movement disorder, MD. To date, evidence of its role or interacting partners within the brain are unknown. The aim of my project is to identify the components of the SGCE complex in the brain using a method called, Tandem affinity purification-mass spectrometry. My goal is to identify the SG-complex in the brain including new members not seen in the complex found in muscle. By determining the proteins which interact with SGCE we will determine the reason mutations in this gene cause MD. Furthermore, the interacting proteins will be candidates for other similar movement disorders, just as the binding partners in muscle cause other forms of muscular dystrophy