Using interesting new computational methods, scientists at MIT are studying the structure of proteins associated with Alzheimer’s and their mutation patterns, research that might discover new soft spots for future drugs against this neurological disorder.
Alzheimer’s is characterized by two kinds of proteins — amyloid and tau — that aggregate in the brain. Stultz and co-author Austin Huang, an HST graduate student, have focused on determining the structure of tau.
But there’s a problem. “Tau is ‘natively unfolded,’ or floppy, so in solution it moves around a lot and can adopt many different structures,” Stultz said [Collin M. Stultz, the leader of the work and the W.M. Keck Associate Professor of Biomedical Engineering in the Department of Electrical Engineering and Computer Science], much like the individual strands in a bowl of cooked spaghetti. Contrast that to the vast majority of other proteins, whose individual strands have similar structures, like the individual strands of uncooked spaghetti.
“With a ‘normal’ protein,” Stultz said, “you can measure the lengths of individual molecules and the average will be a pretty good description of any one.” Tau molecules, however, “are all over the place — they’re so diverse that it’s difficult to get one measurement that describes all of the possible structures.”
That complicates the hunt for specific tau structures associated with Alzheimer’s (not all tau is bad).
Stultz and Huang approached the problem as engineers, breaking it down into steps. Using a method they developed called Energy-minima Mapping and Weighting (EMW), they asked a computer to come up with all possible structures of tau that are consistent with an average set of experimental data.
“We generated lots and lots of structures for both normal tau and a mutant form” associated with an increased risk for Alzheimer’s, Stultz said. By comparing the two sets, the researchers found one structure that was more common in the mutant form — and therefore likely to “play a role in the pathologic process.” That structure, in turn, could then become the target for a new drug.
Press release: MIT zeroes in on Alzheimer’s structures…
To learn more about EMW method and author’s research, head on to the article in PLoS Computational Biology: The Effect of a ΔK280 Mutation on the Unfolded State of a Microtubule-Binding Repeat in Tau
Images: Up: Outline of EMW method, as described in the study. Side: Confocal image of an Alzheimer’s brain showing a region of amyloid plaque. Wellcome Images.