'Molecular mechanisms of polyglutamine aggregation and implications for neurodegeneration'

Event Sponsor: 
Computing, Environment, and Life Sciences
Start Date: 
Aug 24 2009 - 2:00pm to 3:00pm
Building 221 Conference Room A216
Argonne National Laboratory
Rohit Pappu
Speaker(s) Title: 
Associate Professor, Department of Biomedical Engineering, Director, Center for Computational Biolog
Rick Stevens

Huntington's disease is the most prominent of nine CAG repeat disorders. In these disorders, exonic CAG expansions lead to polyglutamine expansions in the coded protein. The ages-of-onset and the severities of disease are inversely correlated with the lengths of polyglutamine expansions. Proteins with polyglutamine expansions are subject to proteolytic processing and fragments rich in polyglutamine are prone to aggregation. How this cascade leads to toxicity remains an unsolved puzzle. Our lab has focused on biophysical aspects of polyglutamine aggregation. Specifically, we have answered questions regarding the driving forces for the aggregation ofpolyglutamine, which is ostensibly hydrophilic in nature. This has yielded some surprising insights regarding the hydrophobic effect. We then focused on the mechanisms of aggregation and have found that the mechanism is considerably more complex than previously thought and involves steps that are both downhill and nucleated. Recent work has focused on the role of sequence contexts on polyglutamine aggregtion and this has yielded surprising results, which may have important implications for understanding the steps involved in connecting the results of mutations to neurodegeneration. The results to be discussed represent a synthesis of work done over the past four years. The tools of interrogation are a combination of theory, simulation, and spectroscopic measurements.

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