NIH. US: 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 [1]. 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 [2].
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.
References:
[1] 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.
[2] 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.