The Role of p38K and protein homeostasis in Limb-Girdle Muscular Dystrophies - Project Summary
Limb-Girdle Muscular Dystrophies (LGMD) are a collection of progressive muscle wasting disorders that result
in muscle weakness in the shoulder and pelvic girdles. Symptoms can vary from reduced movement and
strength through the shoulders, to an abnormal walking gait, to a loss of walking ability. The age of onset
ranges from childhood to late adulthood, with childhood onset typically leading to more severe forms of the
disease. LGMD are caused by mutations in over 30 different genes with diverse functions, though how these
genes interact or how they contribute to a common disease pathology is not well understood. In order to
explore the relationship between various LGMD causative and associated genes, we are utilizing the
genetically tractable model system Drosophila melanogaster, a well-established model for studying muscular
dystrophies. Two LGMD causative/associated genes, BAG-3 and HspB8, are members of a protein quality
control mechanism called the Chaperone Assisted Selective Autophagy (CASA) complex. We now find that the
CASA complex interacts with the stress response p38 MAPK (p38Kb), which is also associated with other
LGMD causing genes. We find that p38Kb and the CASA complex interact to regulate locomotor functions and
to regulate protein aggregation in response to both aging and oxidative stress, two factors associated with
LGMD. In order to identify potential targets of the CASA complex, we have performed a large-scale proteomics
screen and have identified several candidates that have been linked to LGMD or other muscular dystrophies.
Therefore, we hypothesize that p38Kb and the CASA complex regulate the degradation of specific proteins in
response to aging and oxidative stress, and disruption of this process may lead to the development of LGMD.
In addition, we have also screened a library of drug compounds generated by Dr. Andrei Kutateladze at the
University of Denver for the ability to restore the locomotor activity of the p38Kb mutants and have identified a
potential therapeutic compound. We propose to: 1) Analyze the relationship between p38Kb and the CASA
complex in response to oxidative stress, 2) Characterize p38Kb and CASA complex target proteins that
aggregate with age and oxidative stress exposure, and 3) Identify potential LGMD therapeutics, using
Drosophila genetics, behavioral assays, and molecular biology and biochemical approaches. By exploring the
mechanisms that underlie LGMD, we expect to uncover fundamental principles that contribute to disease
pathology and to identify new molecular targets and compounds for the treatment of LGMD and potentially
other muscular dystrophies.
