NUI Maynooth has begun a new research project looking at changes in the cell caused by the crippling disorder, muscular dystrophy, writes Dick Ahlstrom.
An Irish research team hopes to find new treatments for Duchenne muscular dystrophy by studying how the disease damages muscle cells. Understanding the chemical changes caused by the disease should lead to new drug therapies for this degenerative condition.
Muscular Dystrophy Ireland has announced funding for a three-year research project to be headed by Dr Kay Ohlendieck, who takes over this autumn as professor of biology at NUI Maynooth. It will build on work completed by Ohlendieck while working in University College Dublin's Conway Institute of Biomolecular and Biomedical Research, and published earlier this year in the Journal of Applied Physiology.
Muscular dystrophy is a collective term for a variety of neuromuscular conditions, and Duchenne is but one form. All forms are hereditary and characterised by the progressive degeneration and weakening of muscles. Duchenne is the most frequent human gender-specific inherited disease in the Republic occurring in one in 3,000 live male births.
Ohlendieck's UCD research showed what was happening inside muscle cells in Duchenne patients. The work was funded by the EU, the Health Research Board and Enterprise Ireland. The cells lose their ability to handle calcium properly. Calcium is essential for the messaging system used by muscle cells, says Ohlendieck. "If anything goes wrong with this calcium sequencing, the muscle loses strength."
Although the primary genetic abnormality in this disease was established, little was known about what was happening in the cells and whether this might offer new treatments. The team included Kevin Culligan, Louise Glover, Paul Dowling and Niamh Banville. Ohlendieck's group established that the muscle cells were unable to control calcium.
The primary cellular change involves a weakening of the cell surface, says Ohlendieck. For a time the cells seem to be able to cope, but symptoms of muscle weakening begin to emerge when the patient is from three to five years old. "At some stage the regenerative ability of the cell doesn't work any more," he says. The weakened cell membrane lets calcium ions leak into the cell, raising levels and disturbing signalling. "Normally, the calcium levels inside the cell are very low. We thought maybe this failure in calcium regulation caused other effects."
His group found that these cells couldn't clear the excess calcium, a job usually done by calcium regulating proteins. The calcium is usually moved into a storage area inside the cell but in Duchenne patients, this too is altered. "Besides the leaking of the surface membranes, the calcium stores have a lower capacity. More calcium fluxes in and the cell can't remove it to its internal stores."
The team developed a library of antibodies, an element of the immune system designed to target and help identify the calcium regulating proteins. They found three of importance, CLP 150, CLP 170 and CLP 220. They examined changes in the function of these proteins in those with and without the disease, and studied the protein levels.
This work will now continue at Maynooth, with funding from Muscular Dystrophy Ireland, says Ohlendieck. He will use proteomics, the study of all the proteins produced in muscle cells to examine abundances, interactions and so forth. "That might lead to the discovery of a new therapeutic target," he says. The funding was granted, in particular, for "screening for new therapeutic targets in calcium ion handling", he adds.
The object would be to correct abnormal calcium cycling to reduce or eliminate dystrophic symptoms. There might be an opportunity to boost the calcium removal system or repair the surface membrane and so keep excess calcium out, says Ohlendieck. These options could emerge with a better understanding of the complex chemistry taking place inside the cells.