Lack of Aga leads to an accumulation of metabolic by-products, and eventually causes the mental retardation and loss of motor control characteristic of the disease. In normal individuals, Aga breaks down large molecules called glycoproteins into their constituent parts. Signs of AGU typically surface when patients are about 5 years old, said Groffen, when they have trouble learning. The disease quickly progresses, and most patients die when they reach 30 or 35 years of age. By introducing defective Aga genes to mouse embryonic stem cells, Groffen, postdoctoral fellow Vesa Kaartinen, and their colleagues at CHLA developed a line of mice with essentially no functional enzyme.
Stem cells have the unique property of being able to give rise to virtually any type of body tissue.
When these second-generation mice mate with one another, some of their offspring are born with two copies of the defective gene, and fail to produce any Aga enzyme. Examinations of the model mice have also provided some clues as to how AGU causes retardation and motor degeneration. The researchers found that the AGU-mice showed axonal swelling, or an inflammation of long nerve fibers, in an area of the brain known to cause retardation when damaged. He speculates that the swelling arose from impaired motor function caused by nerve damage brought on by the disease. Collaborators in Finland have already fabricated a protein that they hope will be helpful in treating the disease, and will test its effectiveness on the mouse models in the near future.