IU Bloomington to receive $1.2 million for Huntington’s disease research
FOR IMMEDIATE RELEASE
April 29, 2009
BLOOMINGTON, Ind. — The National Institutes of Health has approved a $1.2 million, four-year grant that will allow Indiana University Bloomington scientists to continue their study of Huntington’s disease.
The project, led by IU Bloomington structural biologist Joel Ybe, has focused on the interaction of two proteins, HIP1 (Huntingtin-interacting protein 1) and HIPPI (HIP1-protein interactor), whose association is believed to trigger the death of nervous system cells. Ybe will work with IU Bloomington chemist David Giedroc to characterize the dynamic flexibility of HIP1 by using nuclear magnetic resonance techniques.
The next phase of Ybe’s studies also brings to fore another protein, clathrin, which aids the formation of tiny intracellular bubbles called vesicles.
“The purpose of this RO1 renewal is to define the molecular basis for how the interaction between clathrin-coated vesicles and HIP1 is regulated in healthy cells,” Ybe said. “The successful completion of our upcoming studies will give us an unprecedented atomic-level understanding of HIP1 function in cellular trafficking and my hope is that they will inform and stimulate many areas of Huntington’s disease research.”
Huntington’s disease is a hereditary disorder that causes large numbers of nerve cells to die. About 15,000 people in the U.S. are estimated to have the disease — approximately one person in 20,000. Symptoms include uncontrolled movements, dementia and depression, but these symptoms do not usually appear until the afflicted reach their 30s or 40s. Despite major strides forward in understanding the disease in recent years, there currently is no cure.
The disease begins when the huntingtin protein becomes disassociated from HIP1. Huntingtin’s absence allows another protein, HIPPI, to bind to HIP1. The complex of HIP1 and HIPPI may be responsible for activating other proteins that cause cell death. The loss of large amounts of nerve cells leads to a loss of motor function, and eventually brain function, too.
By understanding the three-dimensional pocket of HIP1 that HIPPI binds to, Ybe says scientists could devise a way to disrupt the binding event in the first place, which could in turn prevent Huntington’s disease from progressing. That disruptor could be a small protein drug that is engineered to fit into the HIPPI binding pocket but does not interfere with the cell’s other natural processes. But such a treatment could only come about by gaining an intimate understanding of the shape and chemical properties of the HIP1 binding pocket.
Specifically, Ybe says, he and his collaborators chief aims are: to learn what destabilizes a key segment of HIP1; to find out whether HIP1’s flexibility affects its ability to interact with another protein, clathrin; and to look at how charged amino acids may play a role in enabling HIPPI to bind to HIP1.
In early 2008, Ybe and Ph.D. student Qian Niu reported in the Journal of Molecular Biology that they had identified key structural features in the HIP1 binding pocket for HIPPI, which Ybe and co-workers will now examine in more detail.
To speak with Joel Ybe, please contact David Bricker, University Communications, at 812-895-9035 or brickerd @ indiana.edu.