Dysferlin is a muscle membrane protein that is mutated in a form of inherited muscular dystrophy. Dysferlin has been shown to be essential for muscle cells to repair acute damage to their surface membrane. Therefore, it is believed that the main cause of muscle breakdown in patients with dysferlin mutations is due to defective membrane repair; a new pathway in the muscular dystrophies. There are many patients with muscular dystrophy in whom the genetic basis for their disorder is unknown. It is likely that some of these patients have defects in other proteins that interact with dysferlin, or are involved in membrane repair pathways.
Microinjection of eggs for in vitro fertilisation is a good example of how most cells can rapidly repair a large hole in their surface membrane. Until the identification of dysferlin, the molecular machinery of membrane resealing was unknown. What was known about membrane repair, is that it is activated by the calcium outside a cell. When the muscle membrane is damaged, calcium gains entry to the inside of a cell, and rapidly activates the fusion of vesicles that form a ‘patch’ to repair a membrane lesion. Dysferlin has many calcium-binding domains, and is proposed to play a key role in this calcium-activated vesicle fusion of membrane repair.
Using dysferlin as the key, we want to unlock the molecular steps required to survive a membrane injury. We have been studying the biology of dysferlin in muscle cells; where it goes, how it behaves, and exactly what role it plays in muscle membrane repair. Modulation of membrane repair holds enormous potential for treatment of muscle disease, and may also be important in other disorders characterised by membrane damage and repair, such as surgery, injury, heart disease and stroke. We have developed novel assays to test therapies that improve recovery from membrane injuring events, with the goal of learning how to modulate membrane resealing pathways for therapeutic treatment of neuromuscular disease, and recovery from cardiac injury or stroke.