Mechanism for prion diseases unfolds

The mechanism by which prion proteins trigger progressive neurodegeneration in spongiform encephalopathies such as Creutzfeldt–Jakob disease (CJD) in humans and mad cow disease in cattle is not known. In two papers in the October 17 issue of Science, Susan Lindquist, director of the Whitehead Institute for Biomedical Research, Cambridge, US, and Jiyan Ma, from Ohio State University, give new insights into how prion proteins kill neurons and how the insoluble, aberrant form of the prion protein (PrP^Sc) arises in the cell.

Mammalian prion (PrP) proteins normally reside on the surface of the cell. But if PrP misfolds during maturation in the endoplasmic reticulum, it is sent to the cytosol via retrograde transport for degradation in the proteasome. If proteasome activity is compromised in any way, however, misfolded PrP accumulates in the cytosol.

"What we were interested in determining is what might be the toxic species and how they might convert," ...