Rohit Pappu, PhD, also collaborates with researchers at the Medical School’s Hope Center Program on Protein Aggregation and Neurodegeneration (HPAN).
A key Hope Center collaborator is Marc Diamond, MD, the David Clayson Professor of Neurology, who has mouse and cellular models in which Pappu’s group can test hypotheses on the effects of gatekeeper molecules, providing a “very immediate” live context of what Pappu’s theoretical computer models predict. Diamond, with Joel Perlmutter, MD, professor of neurology, co-directs the Huntington Disease Clinic at Washington University in the Movement Disorders Section, and sees most of the HD patients there himself.
The Diamond-Pappu collaboration is currently funded by a two-year pilot grant from the Hope Center. Diamond has found over the last several years that the toxic aggregation of the huntingtin protein, the genetic root of the disease, is prevented by its interaction with another protein, profilin, which is regulated by a specific enzyme called a kinase. He is now trying to understand, at a biophysical level, how this interaction can prevent toxic mis-folding, among other things.
Pappu’s computer modeling makes specific predictions about how huntingtin protein structure affects its interactions with profilin, and it can identify specific amino acid changes that should increase or decrease the affinities of the two proteins for one another, and change huntingtin’s toxic aggregation potential. These predictions can be evaluated initially using purified proteins in Pappu’s lab. However, a key test comes when the proteins are studied in cell and animal models of Huntington’s disease, which the Diamond lab provides. Their collaboration is a textbook example of “vertical” integration between computation/biophysical studies and in vivomodeling.
“I think this is a beautiful example of how the Hope Center facilitates collaboration between groups with complementary skills and common interests to achieve synergy in the understanding and treatment of a devastating neurodegenerative disease,” Diamond says.