13 Sep 1999

In the current Nature Cell Biology, Susan Lindquis and Jiang Ma of the Howard Hughes Institute at the University of Chicago report that they were able to produce abnormal prion protein (PrP) conformations from normal PrP, apparently by causing the protein to miss out on processing in the endoplasmic reticulum, consequently collecting in the cytoplasm rather than arriving at its normal destinatino at the cell surface.

By forcing the expression of a full-length, mouse/hamster PrP protein in the cytoplasm of yeast cells, the researchers produced a variant that was detergent insoluble and resistant to proteinase K digestion, a pattern characteristic of the abnormal prion conformation (PrP-Sc) that is thought to underlie prion diseases such as Creutzfeldt-Jakob disease and kuru, as well as bovine spongiform encephalopathy ("mad-cow disease") and scrapie in sheep. They followed this work up by showing that they could produce an abnormal PrP in neural cells by adding reducing agents and antiglycosylation agents to mouse neuroblastoma cells in vitro. By interfering with the oxidative and glycosylation processes of the endoplasmic reticulum, they again generated a detergent-insoluble and protease-resistant PrP.

This accumulation of abnormal PrP in the cytoplasm, say the authors, suggests a model of improper trafficking of proteins and subsequent cytoplasmic aggregation of insoluble proteins or protein fragments that could help explain prion diseases. By the same token, it may have relevance for abnormal protein aggregation in neurodegenerative disease processes such as those in Alzheimer's disease.—Hakon Heimer