The team's findings, which appear June 6 in an advanced online publication of Nature Medicine and online in the journal Cell on June 3, might lead to new treatments for this particular class of muscular dystrophies and other muscle diseases caused by glycosylation defects.
A group of muscular dystrophies, which include Fukuyama Congenital Muscular Dystrophy, Walker-Warburg Syndrome and Muscle-Eye-Brain disease, are caused by mutations in glycosylation enzymes – proteins that add sugars to other proteins. In these diseases, defects in the sugar-adding mechanism disrupt the properties of alpha-dystroglycan, a protein critical for normal muscle function.
Previous work by the UI researchers led by Kevin Campbell, Ph.D., the Roy J. Carver Chair of Physiology and Biophysics and interim head of the department, professor of neurology, and a Howard Hughes Medical Institute (HHMI) Investigator, showed that abnormal glycosylation disrupts alpha-dystroglycan's ability to interact with other proteins and leads to muscle degeneration and brain defects in these muscular dystrophies.
LARGE protein is mutated in patients with congenital muscular dystrophy 1D. In the Nature Medicine article, Campbell and his colleagues examined the effect of restoring expression of LARGE in mice that lacked the protein and found that gene transfer of the protein into this animal model of the disease prevented the development of muscular dystrophy.
More surprisingly, the research team also showed that high levels of LARGE protein expression in cells from patients with the related muscular dystrophies, Fukuyama Congenital Muscular Dystrophy, Walker-Warburg Syndrome and Muscle-Eye-Brain disease, restored the normal functions of alpha-dystroglycan without adversely affecting the cells.
Even though each of these distinct muscular dystrophies is caused by mutations to different sugar-adding proteins, glycosylation of alpha-dystroglycan by LARGE appears to restore the function of alpha-dystroglycan in cells affected by all these diseases.
"The finding that LARGE can restore alpha-dystroglycan function regardless of the type of glycosylation defect is incredibly exciting," Campbell said. "This result may have potential application in the development of therapies for an entire group of muscle diseases."
In the Cell publication, Campbell and his colleagues extended their understanding the interactions between alpha-dystroglycan and LARGE. They determined the molecular details of this interaction and discovered that it is critical for the production of biologically active alpha-dystroglycan, which is necessary to prevent muscle degeneration, a characteristic common to most muscular dystrophies.
Rita Barresi, Ph.D., a research investigator in Campbell's lab, was first author on the Nature Medicine paper, and Motoi Kanagawa, Ph.D., an HHMI postdoctoral fellow in Campbell's lab, and Fumiaki Saito, M.D., a former postdoctoral fellow in Campbell's lab, were joint first authors on the Cell paper. The two research teams, both led by Campbell, included scientists from the Departments of Physiology and Biophysics, Neurology, and Pathology in the UI Carver College of Medicine; The Scripps Research Institute in La Jolla, Calif.; California Pacific Medical Center Research Institute in San Francisco, Calif.; Uppsala University in Sweden; University of Toronto in Ontario, Canada; and the National Center of Neurology and Psychiatry in Tokyo, Japan.
The studies were supported in part by funding from the Muscular Dystrophy Association.
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