The dysferlin interactome application for therapeutic strategies
Research Project
|
01.04.2010
- 31.03.2013
Finding treatment for muscular dystrophies is imperative, as these diseases have a high personal and socioeconomic impact. As skeletal muscles become weak, patients become dependent on their family members, partners and friends for displacements, personal hygiene and feeding. We are interested in the cell biology of human diseases affecting skeletal muscle. Certain features of skeletal muscle fibers, including their large size, make them suitable for investigations of particular aspects of cellular biology such as surface membrane production, maintenance and repair. An important protein implicated in muscle surface membrane repair is dysferlin. Mutations in dysferlin are a frequent cause of the recessively inherited limb girdle muscular dystrophies (LGMD), defining the common subtype of LGMD2B. In addition to LGMD2B, dysferlin mutations also cause Miyoshi Myopathy (MM) and distal anterior compartment myopathy, which are both distal forms of muscular dystrophy. No treatment is currently available for these disabling diseases. The design of treatment strategies for dysferlin deficiency requires knowledge about the cellular function of the dysferlin protein and about its interacting partners. This knowledge is currently scarce. Using affinity purification followed by liquid chromatography/mass spectrometry, we identified a number of proteins in skeletal muscle that showed association with dysferlin. Importantly, we were able to identify the few proteins previously shown to interact with dysferlin, thus indicating the validity of our approach. The newly identified proteins fall into categories of surface membrane proteins, proteins involved in cellular trafficking, signal transduction proteins, as well as proteins involved in protein degradation and quality control. In this application, we propose to study the interaction of dysferlin with selected newly identified binding partners in order to gain insight into the membrane repair mechanism, to understand the trafficking of dysferlin and the degradation pathways used by dysferlin and its mutant variants. This knowledge should allow us to identify cellular targets that could be pharmacologically modified to reconstitute dysferlin expression in patients with dysferlin missense mutations, and, in a broader applicability, to enhance membrane resealing in patients with muscular dystrophies in which the loss of sarcolemmal integrity contributes to the disease process.
