Prion Protein Mutations, Effects on ER Translocation

Donald Tipper, PhD University of Massachusetts

Project Details

Similarities shared by prion diseases and Alzheimer's suggest common pathogenic mechanisms. Both prion diseases and AD result in the accumulation of amyloid proteins in the brain, and this accumulation indicates defects in the folding or processing of these proteins. The fact that mutations in the prion gene cause inherited forms of these diseases reinforces the connection. Dr. Tipper believes that gaining insight into these pathogenic mechanisms is vital to the design of effective treatments. Both the normal form of the prion protein (PrP) and the precursor of Alzheimer's amyloid beta are transmembrane (TM) proteins, meaning that they span the membranes that separate cells or cellular organelles. TM proteins must contain the information that allows them to reach the correct cellular location and orientation to the membrane. Recent evidence suggests that prion pathology results from a defect that causes the prion protein to be inserted backward in the membrane. Dr. Tipper is testing the proposed correlation between the improper insertion of prion proteins and pathogenicity in a yeast organism. He plans to extend these results to mammalian cells. If the correlation is confirmed, the next step would be to investigate the resulting processes that lead to cellular damage and the loss of brain function in AD.