New technique will let doctors better diagnose disease and predict patient outcomes. [Josh Barney/UVA Health System.]
New technique will let doctors better diagnose disease and predict patient outcomes. [Josh Barney/UVA Health System.]

Scientists say they have come up with a novel method that might in the future be used to diagnose disease and predict patient outcomes by measuring small changes in molecular interactions in the body. Potential applications with a genetic component include Alzheimer's, autism, cancer, cardiovascular disease, diabetes, obesity, schizophrenia, and depression, they add.

The team published its research (”Piconewton-Scale Analysis of Ras-BRaf Signal Transduction with Single-Molecule Force Spectroscopy”) in the journal Small.

Mutations are known to alter the molecular interactions that cells use to communicate with each other. J. Julius Zhu, Ph.D., of the University of Virginia School of Medicine, and his international collaborators report the development of a technique to demonstrate that gene mutations responsible for learning problems change molecular interactions by a few piconewtons (one trillionth of a newton). Such changes impact how the cells communicate and, as a result, cognitive ability. By measuring such molecular changes in animal studies, the scientists say they should eventually be able to predict the results of cognitive impairment in human behavior.

“…this study reports a single-molecule force spectroscopic method that enables functional delineation of two interaction sites (≈35 pN and ≈90 pN) between signaling effectors Ras and BRaf in the canonical mitogen-activated protein kinase (MAPK) pathway. This analysis reveals mutations on BRaf at Q257 and A246, two sites frequently linked to cardio-faciocutaneous syndrome, result in ≈10−30 pN alterations in Ras-BRaf intermolecular binding force,” write the investigators. “The magnitude of changes in Ras-BRaf binding force correlates with the size of alterations in protein affinity and in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate receptor (-R)-mediated synaptic transmission in neurons expressing replacement BRaf mutants, and predicts the extent of learning impairments in animals expressing replacement BRaf mutants. These results establish single-molecule force spectroscopy as an effective platform for evaluating the piconewton-level interaction of signaling molecules and predicting the behavior outcome of signal transduction.”

According to the NIH, cardiofaciocutaneous syndrome is a disorder that affects many parts of the body, particularly the heart, facial features, and the skin and hair. People with this condition also have delayed development and intellectual disability, usually ranging from moderate to severe

Dr. Zhu's method relies on “optical tweezers” that employ a laser to hold and move microscopic objects. Using this approach, the scientists can measure the force required to break up intermolecular bonds between the signaling molecules inside the body, allowing them to gauge the effects of gene mutations. The researchers believe the technique has the potential to improve our ability to diagnose mental illness and other diseases.

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