New findings strongly suggest that oculopharyngeal muscular dystrophy (OPMD) can't be explained solely on the basis of the formation of potentially toxic protein clumps in muscle cells. The loss of function of a protein known as PABPN1 appears to be a likely factor in this disease as well.
The findings may lead to new therapeutic strategies.
About the new findings
OPMD primarily affects the muscles of the eyelids and throat, causing difficulty keeping the eyes open and trouble swallowing. Later on in the disease, weakness of the limb muscles also may occur.
The disease is inherited in a dominant fashion, meaning a faulty gene inherited from only one parent is sufficient to cause it. The gene involved carries instructions for the PABPN1 (polyadenylate binding protein nuclear 1) protein.
It's been known for several years that mutations in this gene can cause the protein to be longer than normal and to form clumps in the nuclei of affected muscle cells. Experts have long speculated that these toxic clumps may not be the whole story of the molecular underpinnings of OPMD.
The new findings, published online Dec. 24, 2009, in Human Molecular Genetics, add significant support to the idea that a loss of PABPN1 function, and not just its accumulation as clumps, is key to understanding the disease.
Molecular pharmacologist Grace Pavlath at Emory University in Atlanta (pictured at right in the photo above), who received MDA support for this work, and biochemist Anita Corbett (left), also at Emory, led the study team, which also included other researchers at Emory and an investigator at Sao Paulo State University in Araraquara, Sao Paulo, Brazil.
To see the effects of a loss of PABPN1 on muscle, the investigators conducted experiments on mouse muscle cells depleted of PABPN1. They found that immature muscle cells isolated from different mouse muscle groups failed to mature and proliferate normally without this protein. These activities are necessary for muscle regeneration and maintenance in humans and in mice.
On the molecular level, they found that depletion of the PABPN1 protein in immature muscle cells caused the final genetic instructions (messenger RNA) for various cellular proteins to lack the long, stabilizing tails made of adenine molecules that these RNA strands normally possess.
The messenger RNA strands had tails that were shorter than normal, leaving the RNA vulnerable to premature destruction by the cell and perhaps impairing the cell's ability to use the RNA for protein production even while it lasted.
Meaning for people with OPMD
The more that is known about the causes of OPMD, the better the chances are of developing a therapy to treat it.
The researchers say their results show that the PABPN1 protein appears to be essential for proper muscle regeneration and maintenance in mice and may do the same in humans, but that experiments on muscle tissue taken from people with OPMD are needed to confirm the findings.