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Home > iSGTW - 5 November 2008 > iSGTW Feature - Alzheimers-Parkinsons interaction

Feature - UCSD investigates Alzheimer’s–Parkinson’s interaction

Representation of the cell membrane (green) in "ball-and-stick" form where the balls represent the centers of atoms and the sticks represent the covalent bonds between them.  (See other figure caption for color legend.) The Abeta (orange) is shown in water-accessible form.

Image courtesy of Igor Tsigelny.

In patients with both Alzheimer’s and Parkinson’s, the Parkinson’s disease can progress at an accelerated rate due to an abnormal protein interaction. A team of University of California San Diego (UCSD) researchers is studying this interaction, contributing to the search for a drug that will slow this devastating progression.

Alpha-synuclein (aS) is a protein that accumulates on neural cells in patients with Parkinson’s disease. Through modeling simulations run on San Diego Supercomputing Center (SDSC) resources, the researchers have found that aS can interact abnormally with Abeta amyloid—the protein that causes Alzheimer’s disease when it accumulates in the brain.

When Abeta binds with aS, it creates abnormal hybrid protein complexes—called oligomers—that are better able to attach to neural cell membranes, in turn enhancing the unwanted aS accumulation. The oligomers also create pores, or holes, in the cell membrane, killing the cell. This process accelerates the progression of Parkinson’s disease.

Representation of a cell.  The boundaries of the surface correspond to boundaries of atoms, each shown as an abstracted spherical surface known as a van der Waals surface.  The green represents the cell membrane, orange indicates the Abeta protein; other colors represent the alpha-synuclein (aS) and other related proteins.

Image courtesy of Igor Tsigelny.  

Both aS and Abeta are unstructured proteins, which means they do not have a single stable structure, explained UCSD and SDSC researcher Igor Tsigelny. To better understand how the two proteins interact and aggregate, Tsigelny’s team had to explore all possible structural combinations of the two proteins.

This involved running thousands of extensive molecular dynamics simulations, docking calculations and membrane-contacting surface prediction calculations. The team used BlueGene supercomputers at SDSC (a TeraGrid site) and Argonne National Laboratory, along with SDSC’s DataStar system. The simulations took about 800,000 CPU hours to run, and without grid resources, the team’s work would not have been possible, Tsigelny said.

Once the researchers modeled the protein interaction, they could better study how the aS-Abeta hybrid complex aggregates on neural cells and produces the pores that cause cell death. The team found a set of amino acids that they believe increases the cohesion of oligomers to the neural cell membrane.

“The next step is finding a compound that will interact with these amino acids to prevent aggregation,” Tsigelny said. Such a compound could be used to design a drug that would greatly improve the quality of life for sufferers of these debilitating diseases.

Amelia Williamson, for iSGTW


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