Model of a neurotoxic prion protofibril.
Dept.: Professor, Department of Bioengineering; Professor, Department of Biochemistry; Adjunct, Biomedical & Health Informatics
Neuroscience Focus Group:
There are now over 40 human diseases related to the misfolding and aggregation of specific proteins, for example Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Each protein is related to one or more unique diseases, but the protein aggregates seem to share a common structure: insoluble fibrils with ?-sheets running parallel to the axis (amyloid). Recent advances, however, indicate that the toxic species are soluble oligomers, not the fibrils. Detailed mechanisms of misfolding and structures of toxic aggregates are yet unknown and difficult to discern through experimental methods. So, we use realistic computer simulation methods to characterize the unfolding/misfolding of these proteins. We have found some common features to the intermediate species proposed to correspond to the toxic species. We are actively using the computer-derived structural information to design and experimentally test potential diagnostic and therapeutic agents. We have some very promising designs that target and preferentially bind to the toxic oligomers of transthyretin (system amyloid), Abeta (Alzheimer’s Disease) and amylin (type 2 diabetes). In addition, these same compounds inhibit amyloidosis. We are also testing the ability of these compounds to prevent transmission of transmissible spongiform encephalopathies by binding to the infectious form of the prion protein.