Cytoskeletal Interactions of Dystrophin

University Of Minnesota, Minneapolis MN

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Abstract

? DESCRIPTION (provided by applicant): Dystrophin is a large cytoplasmic protein predominantly expressed in striated muscle. Mutations in dystrophin that abolish or reduce its functionality lead to Duchenne (DMD) or Becker (BMD) muscular dystrophy. Approximately one in every 4000 boys is born with DMD, and all will inevitably become wheelchair-bound and succumb to fatal cardiac arrest or respiratory failure. Current treatment is limited to ventilator support, which prolongs life, and corticosteroids, which also provide benefit, but can cause serious side effects. The majority of DMD or BMD cases are caused by deletions or nonsense mutations, but patients with missense mutations represent a small, yet rapidly growing population who could potentially benefit from personalized therapy approaches. In the current project period, we showed that single amino acid changes associated with DMD-, or BMD-causing missense mutations dramatically impair the stability of dystrophin. We also engineered new transgenic C2C12 myoblasts and mdx mouse lines expressing dystrophins with missense mutations associated with DMD or BMD. We propose in aim 1 to make use of these new tools to investigate whether increasing mutant protein levels by small molecule proteasome inhibitors exacerbates dystrophy or instead provides a potential therapy for this orphaned subpopulation of dystrophinopathy patients. Dystrophin also organizes microtubules into a subsarcolemmal rectilinear lattice that becomes disorganized when the protein is absent, as in the mdx mouse. We and others have recently shown that microtubule disorganization contributes to eccentric contraction induced force drop, which is the most robust phenotype of the mdx mouse. In aim 2, we propose new in vivo rescue experiments to delineate the mechanism by which dystrophin regulates microtubule lattice organization. Finally, in aim 3 we propose physiological and biochemical analyses designed to elucidate the long enigmatic function of the dystrophin carboxy-terminal domain.