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พฤหัสบดี, 18 กันยายน 2008

Researchers discover hybrid abnormal protein with a nanopore that alters neuronal activity

In a collaborative study at the University of California, San Diego, investigators from neurosciences, chemistry, and medicine, as well as the San Diego Supercomputer Center have investigated how proteins involved in neurodegenerative diseases such as Alzheimer and Parkinson disease interact to form unique complexes. Their findings explain why Alzheimer disease patients might develop Parkinson disease, and vice versa. The new and unique molecular structures they discovered can now be used to model and develop new drugs for these devastating neurologic diseases. Their findings are published in the September 3 issue of Public Library of Science (PLoS) ONE.


The team, led by Eliezer Masliah MD, professor of neurosciences and pathology in the UC San Diego School of Medicine, found that “fatal” or abnormal interactions among the a-synuclein protein (involved in Parkinson disease) and Abeta amyloid (which leads to the plaques associated with Alzheimer disease) interact and form unique “hybrid” complexes. These hybrid abnormal protein interactions result in combined neurodegenerative diseases.


“Clinically, we knew that having one neurological disease, such as Alzheimer’s, put patients at risk for another neurological disease in combination with it, for example, Parkinson’s disease or frontotemporal dementia. But as doctors and scientists, we didn’t understand why this occurred until now,” Masliah said. Through computer modeling, they discovered that when the Abeta amyloid and a-synuclein protein interacted they formed a new hybrid protein with a small hole called a nanopore that alters neuronal activity. Masliah described the model of the hybrid complex as being “like looking at a boat with holes in it. Because we can now see the holes, we can learn how to stop the leak.”


In Alzheimer disease, Abeta amyloid accumulates in the intracellular and extracellular spaces of the brain, leading to the formation of plaques. In Parkinson disease, intracellular accumulation of an abundant synaptic protein, a-synuclein, results in the formation of characteristic foreign substances called Lewy bodies. The mechanisms through which Abeta amyloid and a-synuclein interactions might lead to additional neurodegeneration have been the subject of intense scientific investigation, according to Masliah.


Working with researchers at the San Diego Supercomputer Center, Masliah and colleagues, including first author Igor Tsygelni from the Department of Chemistry and Biochemistry, developed a dynamic model using computer simulations. These included the so-called “molecular dynamics process,” which allows insight into molecular motion on an atomic scale. Used to determine the properties of complex systems that contain a vast number of particles through use of numerical methods, molecular dynamics allowed the team to model how the abnormal neuronal proteins docked with other proteins or with cell membranes, and to measure the energies of interaction.


“This sort of modeling, to determine the structure of these complexes, was never before possible,” said Masliah. “With this novel technology, we have come to a new understanding of these combined neurological diseases, and have a model for developing new drugs to treat them.”


These studies were supported by electron microscopy, along with cell and tissue studies of both mice and human brains, to characterize the nature of the interaction between the 2 proteins.


The study was funded in part by the National Institutes of Health, IBM under its Institutes of Innovation program as well as computational support on its BlueGene computers at the San Diego Supercomputer Center and at the Argonne National Laboratory.

Source: News Release
University of California, San Diego Health Sciences
September 3, 2008




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