Science: New Insights Into Prion Diseases?

So-called "prion diseases," such as scrapie and mad cow disease, may begin when certain misformed proteins aren't destroyed by the cell's quality control machinery, according to a new study.

Misfolded proteins, or "prions," have been linked to a variety of neurodegenerative disorders, but the specific role they play in the disorders is unknown. In one study, Jiyan Ma and Susan Lindquist investigated the effects of shutting off the cell's "garbage disposals," complexes of enzymes called proteasomes that destroy misformed proteins. Proteins misfold relatively frequently during their construction in the endoplasmic reticulum, but typically, when they enter the cytosol (the fluid and semi-fluid portion of the cytoplasm), proteasomes destroy them right away. When the authors treated the cells with proteasome inhibitors, they found that harmful prions accumulated in the cytosol. Even after the proteasomes were reactivated, prions continued to accumulate, the researchers report. In a second paper, Ma and colleagues found that even small quantities of cytosolic prions are toxic to neuronal cells. 

The researchers also produced a line of transgenic mice that accumulated prions in their cytoplasm. The mice developed serious neuronal problems, including muscle failure, cerebellar atrophy, and the destruction of the neurons' support cells, known as glia. The authors suggest that proteasome inhibiting drugs be used with caution, and that altering prion trafficking into the cytoplasm may be a potential therapeutic strategy for prion disease.
 
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