Snapshots of Life: Lost Connections in Pompe Disease
Posted on by Dr. Francis Collins
Mistletoe? Holly? Not exactly. This seemingly festive image is a micrograph of nerve cells (green) and nerve-muscle junctions (red) in a mouse model of Pompe disease. Such images are helping researchers learn more about this rare form of muscular dystrophy, providing valuable clues in the ongoing search for better treatments and cures.
People with Pompe disease lack an enzyme that cells depend on to break down a stored sugar, known as glycogen, into smaller glucose molecules that can be readily used for energy. Without enough of this enzyme, called acid alpha-glucosidase (GAA), glycogen can accumulate destructively in the liver, heart, and skeletal muscles, making it increasingly difficult to walk, eat, and even breathe.
Darin Falk, an NIH-funded neuroscientist at the University of Florida, suspected there was more to the muscle weakness seen in Pompe disease than muscles alone. Using a variety of techniques, including the keen microscopy skills recognized by the Federation of American Societies for Experimental Biology’s 2014 BioArt contest, Falk has been busy exploring this hunch.
When Falk used a confocal microscope to examine muscle tissue from the legs and diaphragms of mice with Pompe disease, he saw the nerve-muscle, or neuromuscular, junctions looked strikingly different than those in normal mice. They were more fragmented and showed expansion of the area where nerves contact the muscle (the motor endplate). And, within the nerve cells themselves, Falk detected unusually low levels of certain key proteins that are essential for transmitting the signals that tell muscles to move . Likewise, Falk’s small study of humans with late-onset Pompe disease found evidence that their breathing and movement problems were likely rooted not only in muscle fibers, but also in the nerve cells that control those fibers .
These findings provide a possible explanation for why the current therapy for Pompe disease—a biweekly infusion of the missing enzyme—slows, but fails to halt the disease process. While it is relatively easy to get replacement enzyme therapy into muscle cells, delivery to nerve cells poses a much tougher challenge.
So, Falk’s team is now collaborating with Barry Byrne, director of the University of Florida’s Powell Gene Therapy Center, who is conducting human clinical trials to test possible new treatments for this often-fatal disease. In addition to the enzyme infusions, Byrne is working on gene therapy with the aim of delivering a healthy version of the GAA gene into many types of cells, including motor neurons, throughout the body. By doing so, Falk and Byrne are hopeful that they will someday be able to enhance communication at neuromuscular junctions, leading to improvements in heart, breathing, and muscle function for those with Pompe disease.
 Peripheral nerve and neuromuscular junction pathology in Pompe disease. Falk DJ, Todd AG, Lee S, Soustek MS, ElMallah MK, Fuller DD, Notterpek L, Byrne BJ. Hum Mol Genet. 2014 Sep 12.
 Altered activation of the tibialis anterior in individuals with Pompe disease: Implications for motor unit dysfunction. Corti M, Smith BK, Falk DJ, Lee Ann L, Fuller DD, Subramony SH, Byrne BJ, Christou EA. Muscle Nerve. 2014 Sep 3.
Pompe Disease (NINDS)
Falk Research Lab, University of Florida, Gainesville
Byrne Research Lab, University of Florida, Gainesville
BioArt, Federation of American Societies for Experimental Biology
NIH support: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Heart, Lung, and Blood Institute, and National Institute of Child Health and Human Development