Glenn Millhauser, distinguished professor of chemistry and biochemistry at UC Santa Cruz, has received a $1.8 million grant from the Maximizing Investigators' Research Award (MIRA) program of the National Institute for General Medical Science (NIGMS). The prestigious five-year grant provides flexible, long-term funding for Millhauser's research program focused on understanding the role of the prion protein in neurodegenerative diseases.
Prions are misfolded proteins that cause fatal neurodegenerative brain disorders such as Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy in cows ("mad cow disease"), and chronic wasting disease in deer and elk. The normal cellular prion protein is found in all mammals as a membrane protein on the surfaces of various cell types, including neurons in the brain. Misfolded prions are transmissible and can induce the normal form of the protein to adopt the abnormal, toxic shape.
Over the past two decades, Millhauser's lab has made significant progress in understanding the structure and function of the normal cellular prion protein. His research has shown that the protein binds metal ions, specifically copper and zinc, and controls the distribution of these essential elements in the brain. Importantly, he and his collaborators have also shown that the protein has two domains, one of which has toxic effects that drive brain cell damage when not controlled by the other domain.
"There are two halves to the protein--one half produces toxicity, and the other half is a regulatory domain that keeps the protein in a nontoxic state," Millhauser explained. "Our research shows that the interaction between the two domains is controlled by the binding of physiological metal ions."
Ongoing research in his lab is aimed at understanding the nature of the toxic signal, as well as the normal function of the toxic domain when it is properly regulated. Millhauser is also interested in following up on findings by other researchers suggesting that the prion protein may be involved in Alzheimer's disease. Studies have shown that aggregates of a protein called amyloid beta, which are associated with Alzheimer's disease, bind to the cellular prion protein.
"There is a lot of effort now to understand how amyloid-beta aggregates interact with the prion protein," Millhauser said.
Another interaction of interest to his lab is between the cellular prion protein and receptors for the neurotransmitter glutamate. This interaction may be a key to the normal function of the prion protein, Millhauser said.
Millhauser's lab uses advanced magnetic resonance spectroscopy to analyze the structure and function of complex proteins. In the prion research, he works closely with a team at Boston University School of Medicine led by Dr. David Harris.
The MIRA grant provides extended funding with the needed flexibility to pursue new leads and make efficient progress in this highly important and rapidly changing biomedical field.
