Engineer Investigates Enzyme Link to Neurological Disease
Several neurologically based afflictions, such as Huntington’s, Parkinson’s, and Alzheimer diseases, have been correlated to a higher than normal presence of a specific type of enzymes, called transglutaminases (TGase) in the human body. TGases, whose function is to catalyze covalent bonds among proteins, are commonly found in several different human tissues.
In the presence of unusually high levels of these enzymes, some proteins tend to form denser clusters than normal in vivo. If the aggregates grow in size, it can lead to a build-up of insoluble plaques that can block neurovascular transport and cause neural cell death.
“If higher TGase concentrations in cerebrospinal fluid and in the brain lead to protein agglomeration, then their inhibition could reduce symptoms, delay the onset of agglomeration, and maintain viable neural cell health extending the quality of life for those afflicted,” hypothesizes Brian Love, a professor of materials science and engineering (MSE) at Virginia Tech.
Love, who focuses his research on tissue and cell engineering, and Elena Fernandez Burguera, a post-doctoral research associate, are evaluating specific therapies to fight the abnormally high TGase binding. Based upon the prior work of several others who are conducting clinical trials, Love and Burguera are developing an in vitro model to evaluate the ability of several inhibitors to block protein aggregation by TGases.
Again, based on the work of other scientists, “several compounds show some positive effects,” Love says. These include creatine, cystamine hydrochloride, and a few others. “The development of an inhibition protocol may help test the efficacy of other inhibitors as well,” the engineer adds.
The Virginia Tech researchers are looking at the enzymatic binding of protein-bound polystyrene particles as models. Groups of particles are dispersed in calcium-rich aqueous solutions containing TGases. Once mixed, the particle binding begins. The bigger agglomerates attempt to settle out of the solution, and Love and Burguera track particle sedimentation.
The tracking method, called Z-axis Translating Laser Light Scattering (ZATLLS), is unique to Virginia Tech and based on key concepts in transport phenomena. It has been used to gauge how other complex fluids, such as paints and sealants, are dispersed. Now Love and Burguera are resolving when protein coated particles are effectively dispersed in vitro and under what conditions they are unstable enough to agglomerate.
They track in situ sedimentation of protein-coated particles exposed to transglutaminase, both in the presence of and without transglutaminase inhibitors. “We can use ZATLLS to resolve whether inhibitors prevent agglomeration of protein coated particles by TGase if the inhibitors lower the particle sedimentation velocity,” Love says. “Our goal is to find the safest and most effective inhibitors that prevent the agglomeration-based crosslinking found throughout these neurological disorders.”
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